{ "version": "20260604_core_validation_v45", "report_id": "0af107408c52712a", "input": { "raw_sequence": "AUGCUACUGACUGA", "helm_notation": "", "sequence_input_mode": "plain sequence", "canonical_dna_sequence": "ATGCTACTGACTGA", "invalid_sequence_characters": [], "target": "PCSK9", "modification": "GalNAc", "delivery": "GalNAc", "endpoint": "hepatic", "species": "human", "cell_type": "" }, "sequence_features": { "length": 14, "seed_2_8": "TGCTACT", "unique_7mer_windows_first_12": [ "ATGCTAC", "TGCTACT", "GCTACTG", "CTACTGA", "TACTGAC", "ACTGACT", "CTGACTG", "TGACTGA" ], "contains_ambiguous_base": false, "status": "valid seed-aware input" }, "summary": { "evidence_supported_concerns": 7, "evidence_gap_concerns": 0, "not_assessable_concerns": 0, "release_records_considered": 25, "candidate_gap_records_considered": 36, "interpretation": "Evidence-dense safety review required." }, "triage_policy": { "prediction_mode": "no de novo safety prediction", "evidence_boundary": "Report links user-provided design features to curator-verified release evidence and candidate curation gaps.", "citable_rows": "Only records marked curator-verified release evidence should be cited." }, "dossier": { "title": "OligoVigil Safety Evidence Dossier", "one_sentence_value": "Turns a candidate oligonucleotide safety question into a citable, source-grounded evidence packet.", "primary_use": "preclinical safety review, oligonucleotide design triage, benchmark reuse, and reviewer-auditable provenance inspection", "not_for": "clinical recommendation, de novo safety prediction, or replacement of transcriptome alignment/toxicology review", "sections": [ { "section": "Design context", "purpose": "Normalize user-provided sequence, HELM-derived bases, target, chemistry, delivery, tissue/species, and endpoint focus." }, { "section": "Risk matrix", "purpose": "Separate evidence-supported concerns, contextual evidence, candidate gaps, and non-assessable concerns." }, { "section": "Evidence graph", "purpose": "Connect design features, safety concerns, release records, sources, and candidate gaps." }, { "section": "Provenance packet", "purpose": "Expose source location, PMID/DOI/PMCID, curator audit, grade policy, and citable record links." }, { "section": "Benchmark reuse", "purpose": "Identify Grade A/B records that can be reused in fixed reference split comparisons." } ] }, "risk_matrix": [ { "concern_id": "hematology_platelet", "domain": "toxicity", "concern": "Hematology and platelet safety", "evidence_state": "evidence-supported concern", "release_records": 20, "benchmark_eligible_records": 18, "candidate_records": 20, "top_release_records": [ { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 313, "canonical_name": "PCSK9; 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source title: Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates.", "triage_match_score": 3, "triage_matched_terms": "galnac, liver, human" }, { "id": 1897, "queue_id": 4523, "pmid": "33928571", "doi": "10.1007/978-1-0716-1298-9_6", "evidence_domain": "toxicity", "candidate_modality": "siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: siRNA Design and GalNAc-Empowered Hepatic Targeted Delivery.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "siRNA Design and GalNAc-Empowered Hepatic Targeted Delivery.", "triage_match_score": 3, "triage_matched_terms": "galnac, hepatic, liver" }, { "id": 2224, "queue_id": 5268, "pmid": "40080657", "doi": "10.1021/acschembio.5c00039", "evidence_domain": "toxicity", "candidate_modality": "siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Optimizing Peptide-Conjugated Lipid Nanoparticles for Efficient siRNA Delivery across the Blood-Brain Barrier and Treatment of Glioblastoma Multiforme.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Optimizing Peptide-Conjugated Lipid Nanoparticles for Efficient siRNA Delivery across the Blood-Brain Barrier and Treatment of Glioblastoma Multiforme.", "triage_match_score": 3, "triage_matched_terms": "liver, ast, blood" }, { "id": 3380, "queue_id": 8202, "pmid": "41430089", "doi": "10.1038/s41598-025-32407-x", "evidence_domain": "toxicity", "candidate_modality": "ASO/siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Delivery of lipid nanoparticles containing small interfering RNA targeting transmembrane serine protease 4 in a human gastric cancer model using nude mice.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Delivery of lipid nanoparticles containing small interfering RNA targeting transmembrane serine protease 4 in a human gastric cancer model using nude mice.", "triage_match_score": 3, "triage_matched_terms": "liver, ast, human" }, { "id": 3665, "queue_id": 8893, "pmid": "40633772", "doi": "10.1016/j.jconrel.2025.114018", "evidence_domain": "toxicity", "candidate_modality": "ASO", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Low-frequency ultrasound-mediated blood-brain barrier opening enables non-invasive lipid nanoparticle RNA delivery to glioblastoma.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Low-frequency ultrasound-mediated blood-brain barrier opening enables non-invasive lipid nanoparticle RNA delivery to glioblastoma.", "triage_match_score": 3, "triage_matched_terms": "liver, ast, blood" } ], "rationale": "20 curator-verified release records and 20 candidate gap records matched this concern.", "recommended_action": "Check platelet, coagulation, and hematology endpoints before dose escalation.", "release_endpoint": "/api/evidence_records?domain=toxicity&q=platelet&limit=20", "candidate_endpoint": "/api/curation_candidates?domain=toxicity&q=platelet&limit=20" }, { "concern_id": "hepatobiliary_toxicity", "domain": "toxicity", "concern": "Hepatic and hepatobiliary toxicity", "evidence_state": "evidence-supported concern", "release_records": 20, "benchmark_eligible_records": 18, "candidate_records": 20, "top_release_records": [ { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 313, "canonical_name": "PCSK9; 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matched derived terms: toxicity, toxic, renal; source title: Mitigation of Cisplatin-Induced Nephrotoxicity and Augmentation of Anticancer Potency via Tea Polyphenol Nanoparticles' Codelivery of siRNA from CRISPR/Cas9 Screened Targets.", "suggested_evidence_grade": "B", "confidence_label": "high_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Mitigation of Cisplatin-Induced Nephrotoxicity and Augmentation of Anticancer Potency via Tea Polyphenol Nanoparticles' Codelivery of siRNA from CRISPR/Cas9 Screened Targets.", "triage_match_score": 4, "triage_matched_terms": "liver, renal, nephrotoxicity, nephrotoxic" }, { "id": 178, "queue_id": 388, "pmid": "38742636", "doi": "10.1093/nar/gkae350", "evidence_domain": "toxicity", "candidate_modality": "siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates.", "triage_match_score": 3, "triage_matched_terms": "galnac, liver, human" }, { "id": 1897, "queue_id": 4523, "pmid": "33928571", "doi": "10.1007/978-1-0716-1298-9_6", "evidence_domain": "toxicity", "candidate_modality": "siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: siRNA Design and GalNAc-Empowered Hepatic Targeted Delivery.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "siRNA Design and GalNAc-Empowered Hepatic Targeted Delivery.", "triage_match_score": 3, "triage_matched_terms": "galnac, hepatic, liver" } ], "rationale": "20 curator-verified release records and 20 candidate gap records matched this concern.", "recommended_action": "Check kidney biomarkers, histopathology, and chemistry/dose context.", "release_endpoint": "/api/evidence_records?domain=toxicity&q=renal&limit=20", "candidate_endpoint": "/api/curation_candidates?domain=toxicity&q=renal&limit=20" }, { "concern_id": "sequence_seed_offtarget", "domain": "offtarget", "concern": "Seed and hybridization off-target evidence", "evidence_state": "evidence-supported concern", "release_records": 20, "benchmark_eligible_records": 20, "candidate_records": 20, "top_release_records": [ { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 1, "canonical_name": "SNA-modified GalNAc-siRNA panel from PMID 41994868", "modality": "siRNA", "target_gene_symbol": "TTR", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "A", "source_location": "Results > Analysis of miRNA-like off-target activity in a luciferase reporter assay; paragraph 3", "source_document_id": 1031, "source_title": "Acyclic serinol nucleic acid modification of siRNAs overcomes seed region mediated off-target effects while maintaining potency.", "pmid": "41994868", "source_pmcid": "PMC13096799", "doi": "10.1093/nar/gkag345", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41994868/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "The greatest impact of SNA modification was observed when included at position g7 in si-50, with a relative off-target IC50 increase of ~260-fold over the parent si-47.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "galnac, seed, seed-mediated, seed region, mirna-like, offtarget", "record": "offtarget:1" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 331, "canonical_name": "F7-1 siRNA", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "B", "source_location": "Results > Enrichment analysis of seed region matches in F7-1 off-target genes; paragraph 13", "source_document_id": 15845, "source_title": "Single base mismatches in the mRNA target site allow specific seed region-mediated off-target binding of siRNA targeting human coagulation factor 7.", "pmid": "22258146", "source_pmcid": "PMC3342946", "doi": "10.4161/rna.9.1.18121", "source_url": "https://pubmed.ncbi.nlm.nih.gov/22258146/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Accept B: PubMed abstract gives a direct abstract-level signal for seed-mediated off-target effect in F7-1 siRNA; no full passage, so curator kept confidence limited.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "human, seed, seed-mediated, seed region, offtarget, mismatch", "record": "offtarget:331" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 60, "canonical_name": "siRNA-based", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "A", "source_location": "Results > Minimal off-target activity of GalNAc-siCIDEB; paragraph 8", "source_document_id": 9324, "source_title": "Targeting CIDEB alleviates liver steatosis and fibrosis in mouse MASH models.", "pmid": "40503175", "source_pmcid": "PMC12156227", "doi": "10.1016/j.omtn.2025.102567", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40503175/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "To evaluate the off-target effects of GalNAc-siCIDEB, we first conducted whole-transcriptome RNA sequencing (RNA-seq) analysis in primary rat hepatocytes.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "galnac, liver, seed, seed-mediated, offtarget", "record": "offtarget:60" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 8, "canonical_name": "GalNAc-siRNA panel from PMID 29459660", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "A", "source_location": "Results > siRNA off-targets are enriched for seed complementarity; paragraph 17", "source_document_id": 2058, "source_title": "Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.", "pmid": "29459660", "source_pmcid": "PMC5818625", "doi": "10.1038/s41467-018-02989-4", "source_url": "https://pubmed.ncbi.nlm.nih.gov/29459660/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Consistent with these data, global transcriptome profiling by RNAseq shows RISC loading-dependent downregulation of RNAs enriched for a seed match to the antisense but not the sense strand of GalNAc-siRNAs.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "galnac, hepatotoxicity, seed, seed-mediated, offtarget", "record": "offtarget:8" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 345, "canonical_name": "siRNA-5", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "B", "source_location": "Results > siRNA off-targets are enriched for seed complementarity; paragraph 17", "source_document_id": 2058, "source_title": "Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.", "pmid": "29459660", "source_pmcid": "PMC5818625", "doi": "10.1038/s41467-018-02989-4", "source_url": "https://pubmed.ncbi.nlm.nih.gov/29459660/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Consistent with these data, global transcriptome profiling by RNAseq shows RISC loading-dependent downregulation of RNAs enriched for a seed match to the antisense but not the sense strand of GalNAc-siRNAs.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "galnac, hepatotoxicity, seed, seed-mediated, offtarget", "record": "offtarget:345" } ], "top_candidate_records": [ { "id": 16930, "queue_id": 46099, "pmid": "22258146", "doi": "10.4161/rna.9.1.18121", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed title", "matched_terms": "off-target;seed;mismatch", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=off-target, seed, mismatch; source title: Single base mismatches in the mRNA target site allow specific seed region-mediated off-target binding of siRNA targeting human coagulation factor 7.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Single base mismatches in the mRNA target site allow specific seed region-mediated off-target binding of siRNA targeting human coagulation factor 7.", "triage_match_score": 5, "triage_matched_terms": "human, seed, seed region, offtarget, mismatch" }, { "id": 32407, "queue_id": 61576, "pmid": "11687950", "doi": "10.1038/sj.neo.7900185", "evidence_domain": "offtarget", "candidate_modality": "ASO", "source_location": "PubMed title", "matched_terms": "microarray", "candidate_signal": "offtarget candidate; derived PubMed query=aso_oligo_offtarget; terms=microarray; source title: Genome-wide screening of genes showing altered expression in liver metastases of human colorectal cancers by cDNA microarray.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Genome-wide screening of genes showing altered expression in liver metastases of human colorectal cancers by cDNA microarray.", "triage_match_score": 5, "triage_matched_terms": "liver, alt, ast, human, offtarget" }, { "id": 16768, "queue_id": 45937, "pmid": "27308945", "doi": "10.1089/scd.2015.0383", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed query-level off-target/specificity candidate; exact source location requires curator check", "matched_terms": "sirna;rnai;off-target", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=sirna, rnai, off-target; source title: Modeling Nonalcoholic Fatty Liver Disease with Human Pluripotent Stem Cell-Derived Immature Hepatocyte-Like Cells Reveals Activation of PLIN2 and Confirms Regulatory Functions of Peroxisome Proliferator-Activated Receptor Alpha.", "suggested_evidence_grade": "C", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Modeling Nonalcoholic Fatty Liver Disease with Human Pluripotent Stem Cell-Derived Immature Hepatocyte-Like Cells Reveals Activation of PLIN2 and Confirms Regulatory Functions of Peroxisome Proliferator-Activated Receptor Alpha.", "triage_match_score": 4, "triage_matched_terms": "liver, hepatocyte, human, offtarget" }, { "id": 17756, "queue_id": 46925, "pmid": "36006421", "doi": "10.18632/aging.204242", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed query-level off-target/specificity candidate; exact source location requires curator check", "matched_terms": "sirna;rnai;off-target", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=sirna, rnai, off-target; source title: Gene expression profile of human colorectal cancer identified NKTR as a biomarker for liver metastasis.", "suggested_evidence_grade": "C", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Gene expression profile of human colorectal cancer identified NKTR as a biomarker for liver metastasis.", "triage_match_score": 4, "triage_matched_terms": "liver, ast, human, offtarget" }, { "id": 17844, "queue_id": 47013, "pmid": "18646787", "doi": "10.1021/pr800153s", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed query-level off-target/specificity candidate; exact source location requires curator check", "matched_terms": "sirna;rnai;off-target", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=sirna, rnai, off-target; source title: Quantitative proteomic signature of liver cancer cells: tissue transglutaminase 2 could be a novel protein candidate of human hepatocellular carcinoma.", "suggested_evidence_grade": "C", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Quantitative proteomic signature of liver cancer cells: tissue transglutaminase 2 could be a novel protein candidate of human hepatocellular carcinoma.", "triage_match_score": 4, "triage_matched_terms": "liver, hepatocellular, human, offtarget" } ], "rationale": "20 curator-verified release records and 20 candidate gap records matched this concern.", "recommended_action": "Run transcriptome/3'UTR seed-match screening before claiming sequence-specific safety.", "release_endpoint": "/api/evidence_records?domain=offtarget&q=seed&limit=20", "candidate_endpoint": "/api/curation_candidates?domain=offtarget&q=seed&limit=20" }, { "concern_id": "transcriptome_offtarget", "domain": "offtarget", "concern": "Transcriptome-level off-target readout", "evidence_state": "evidence-supported concern", "release_records": 20, "benchmark_eligible_records": 20, "candidate_records": 20, "top_release_records": [ { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 4, "canonical_name": "APP-AON/ATXN3-AON/HTT-AON panel from PMID 41066632", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hybridization/mismatch off-target effect", "evidence_label": "hybridization/mismatch off-target effect", "evidence_grade": "A", "source_location": "Results > Hybridization-dependent off-target splicing events do not play a major role after transfection; paragraph 19", "source_document_id": 1442, "source_title": "Determining off-target effects of splice-switching antisense oligonucleotides using short read RNAseq in neuronally differentiated human induced pluripotent stem cells.", "pmid": "41066632", "source_pmcid": "PMC12581821", "doi": "10.1093/hmg/ddaf153", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41066632/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "In this study, we used three different splice-switching AONs targeting three different human transcripts to study their transcriptome-wide, hybridization-dependent off-target effects with short read RNAseq.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "human, rna, seq, offtarget, mismatch, hybridization", "record": "offtarget:4" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 333, "canonical_name": "ATXN3-AON", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hybridization/mismatch off-target effect", "evidence_label": "hybridization/mismatch off-target effect", "evidence_grade": "B", "source_location": "Results > Hybridization-dependent off-target splicing events do not play a major role after transfection; paragraph 19", "source_document_id": 1442, "source_title": "Determining off-target effects of splice-switching antisense oligonucleotides using short read RNAseq in neuronally differentiated human induced pluripotent stem cells.", "pmid": "41066632", "source_pmcid": "PMC12581821", "doi": "10.1093/hmg/ddaf153", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41066632/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "In this study, we used three different splice-switching AONs targeting three different human transcripts to study their transcriptome-wide, hybridization-dependent off-target effects with short read RNAseq.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "human, rna, seq, offtarget, mismatch, hybridization", "record": "offtarget:333" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 338, "canonical_name": "siCD46 siRNA", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hybridization/mismatch off-target effect", "evidence_label": "hybridization/mismatch off-target effect", "evidence_grade": "B", "source_location": "RESULTS > Comparison of site-specific alterations in siRNA or target sequence; paragraph 15", "source_document_id": 15336, "source_title": "Analysis of siRNA specificity on targets with double-nucleotide mismatches.", "pmid": "18420656", "source_pmcid": "PMC2396434", "doi": "10.1093/nar/gkn190", "source_url": "https://pubmed.ncbi.nlm.nih.gov/18420656/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Accept C: PubMed abstract gives a weak abstract-level signal for hybridization/mismatch off-target effect in siCD46 siRNA; no full passage, so curator kept confidence limited.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "alt, rna, seq, offtarget, mismatch, hybridization", "record": "offtarget:338" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 47, "canonical_name": "unspecified antisense oligonucleotide", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "transcriptome-level off-target effect", "evidence_label": "transcriptome-level off-target effect", "evidence_grade": "B", "source_location": "PubMed abstract", "source_document_id": 2216, "source_title": "Using RNA-seq to Assess Off-Target Effects of Antisense Oligonucleotides in Human Cell Lines.", "pmid": "33314011", "source_pmcid": null, "doi": "10.1007/s40291-020-00504-4", "source_url": "https://pubmed.ncbi.nlm.nih.gov/33314011/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-linked derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "METHODS: We extend recent studies by investigating the off-target profile of two 17-mer antisense oligonucleotides in two distinct human cell lines by a whole-transcriptome study using RNA sequencing.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "human, transcriptome, rna-seq, rna, seq, offtarget", "record": "offtarget:47" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 6, "canonical_name": "DM1 ASO panel from PMID 37200862", "modality": "ASO", "target_gene_symbol": "DMPK", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "transcriptome-level off-target effect", "evidence_label": "transcriptome-level off-target effect", "evidence_grade": "A", "source_location": "Results > RNA-seq reveals activation of the interferon response by all ASOs and additional off-target effects on gene expression by the repeat gapmer; paragraph 3", "source_document_id": 1481, "source_title": "Block or degrade? Balancing on- and off-target effects of antisense strategies against transcripts with expanded triplet repeats in DM1.", "pmid": "37200862", "source_pmcid": "PMC10185704", "doi": "10.1016/j.omtn.2023.04.010", "source_url": "https://pubmed.ncbi.nlm.nih.gov/37200862/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "by performing RNA sequencing (RNA-seq) for cells after ASO treatment, we assessed both on- and off-target effects of the ASOs on a transcriptome-wide level.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "transcriptome, rna-seq, rna, seq, offtarget", "record": "offtarget:6" } ], "top_candidate_records": [ { "id": 8209, "queue_id": 28349, "pmid": "38887517", "doi": "10.3389/fcell.2024.1416780", "evidence_domain": "offtarget", "candidate_modality": "ASO/siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "offtarget candidate from queue only; source title: Integrating scRNA-seq and bulk RNA-seq to explore the differentiation mechanism of human nail stem cells mediated by onychofibroblasts.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Integrating scRNA-seq and bulk RNA-seq to explore the differentiation mechanism of human nail stem cells mediated by onychofibroblasts.", "triage_match_score": 6, "triage_matched_terms": "ast, human, rna-seq, rna, seq, offtarget" }, { "id": 1028, "queue_id": 2430, "pmid": "39045328", "doi": "10.3389/fgene.2024.1397502", "evidence_domain": "offtarget", "candidate_modality": "ASO/siRNA", "source_location": "PubMed title", "matched_terms": "transcriptome", "candidate_signal": "offtarget candidate; matched derived terms: transcriptome; source title: Alternative splicing responses to salt stress in Glycyrrhiza uralensis revealed by global profiling of transcriptome RNA-seq datasets.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Alternative splicing responses to salt stress in Glycyrrhiza uralensis revealed by global profiling of transcriptome RNA-seq datasets.", "triage_match_score": 6, "triage_matched_terms": "alt, transcriptome, rna-seq, rna, seq, offtarget" }, { "id": 1030, "queue_id": 2434, "pmid": "38966147", "doi": "10.3389/fpls.2024.1394223", "evidence_domain": "offtarget", "candidate_modality": "ASO/siRNA", "source_location": "PubMed abstract sentence 4", "matched_terms": "transcriptome", "candidate_signal": "offtarget candidate; matched derived terms: transcriptome; source title: RNA-seq analysis reveals transcriptome reprogramming and alternative splicing during early response to salt stress in tomato root.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "RNA-seq analysis reveals transcriptome reprogramming and alternative splicing during early response to salt stress in tomato root.", "triage_match_score": 6, "triage_matched_terms": "alt, transcriptome, rna-seq, rna, seq, offtarget" }, { "id": 15221, "queue_id": 44390, "pmid": "38958110", "doi": "10.1002/adma.202404784", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed abstract sentence 7", "matched_terms": "transcriptome", "candidate_signal": "offtarget candidate; matched derived terms: transcriptome; source title: Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.", "triage_match_score": 6, "triage_matched_terms": "liver, hepatocellular, ast, transcriptome, rna, offtarget" }, { "id": 18034, "queue_id": 47203, "pmid": "31408249", "doi": "10.1002/jgm.3117", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed title", "matched_terms": "rna-seq;mirna", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=rna-seq, mirna; source title: Identification of human miR-1839-5p by small RNA-seq, a miRNA enriched in neoplastic tissues.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Identification of human miR-1839-5p by small RNA-seq, a miRNA enriched in neoplastic tissues.", "triage_match_score": 6, "triage_matched_terms": "ast, human, rna-seq, rna, seq, offtarget" } ], "rationale": "20 curator-verified release records and 20 candidate gap records matched this concern.", "recommended_action": "Prioritize observed transcriptome evidence and separate it from computational-only context.", "release_endpoint": "/api/evidence_records?domain=offtarget&q=transcriptome&limit=20", "candidate_endpoint": "/api/curation_candidates?domain=offtarget&q=transcriptome&limit=20" } ], "matched_release_records": [ { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 1, "canonical_name": "SNA-modified GalNAc-siRNA panel from PMID 41994868", "modality": "siRNA", "target_gene_symbol": "TTR", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "A", "source_location": "Results > Analysis of miRNA-like off-target activity in a luciferase reporter assay; paragraph 3", "source_document_id": 1031, "source_title": "Acyclic serinol nucleic acid modification of siRNAs overcomes seed region mediated off-target effects while maintaining potency.", "pmid": "41994868", "source_pmcid": "PMC13096799", "doi": "10.1093/nar/gkag345", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41994868/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "The greatest impact of SNA modification was observed when included at position g7 in si-50, with a relative off-target IC50 increase of ~260-fold over the parent si-47.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "galnac, seed, seed-mediated, seed region, mirna-like, offtarget", "record": "offtarget:1" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 4, "canonical_name": "APP-AON/ATXN3-AON/HTT-AON panel from PMID 41066632", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hybridization/mismatch off-target effect", "evidence_label": "hybridization/mismatch off-target effect", "evidence_grade": "A", "source_location": "Results > Hybridization-dependent off-target splicing events do not play a major role after transfection; paragraph 19", "source_document_id": 1442, "source_title": "Determining off-target effects of splice-switching antisense oligonucleotides using short read RNAseq in neuronally differentiated human induced pluripotent stem cells.", "pmid": "41066632", "source_pmcid": "PMC12581821", "doi": "10.1093/hmg/ddaf153", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41066632/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "In this study, we used three different splice-switching AONs targeting three different human transcripts to study their transcriptome-wide, hybridization-dependent off-target effects with short read RNAseq.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "human, rna, seq, offtarget, mismatch, hybridization", "record": "offtarget:4" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 6, "canonical_name": "DM1 ASO panel from PMID 37200862", "modality": "ASO", "target_gene_symbol": "DMPK", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "transcriptome-level off-target effect", "evidence_label": "transcriptome-level off-target effect", "evidence_grade": "A", "source_location": "Results > RNA-seq reveals activation of the interferon response by all ASOs and additional off-target effects on gene expression by the repeat gapmer; paragraph 3", "source_document_id": 1481, "source_title": "Block or degrade? Balancing on- and off-target effects of antisense strategies against transcripts with expanded triplet repeats in DM1.", "pmid": "37200862", "source_pmcid": "PMC10185704", "doi": "10.1016/j.omtn.2023.04.010", "source_url": "https://pubmed.ncbi.nlm.nih.gov/37200862/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "by performing RNA sequencing (RNA-seq) for cells after ASO treatment, we assessed both on- and off-target effects of the ASOs on a transcriptome-wide level.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "transcriptome, rna-seq, rna, seq, offtarget", "record": "offtarget:6" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 60, "canonical_name": "siRNA-based", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "A", "source_location": "Results > Minimal off-target activity of GalNAc-siCIDEB; paragraph 8", "source_document_id": 9324, "source_title": "Targeting CIDEB alleviates liver steatosis and fibrosis in mouse MASH models.", "pmid": "40503175", "source_pmcid": "PMC12156227", "doi": "10.1016/j.omtn.2025.102567", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40503175/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "To evaluate the off-target effects of GalNAc-siCIDEB, we first conducted whole-transcriptome RNA sequencing (RNA-seq) analysis in primary rat hepatocytes.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "galnac, liver, seed, seed-mediated, offtarget", "record": "offtarget:60" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 66, "canonical_name": "Sequence 1 (recovered B2 from PMID:28918038, curator:CM)", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "unspecified", "modification_annotation_status": "unspecified", "category": "transcriptome-level off-target effect", "evidence_label": "transcriptome-level off-target effect", "evidence_grade": "A", "source_location": "Results > High Confirmation Rate of In Silico Predicted OTEs in Mouse Liver; paragraph 14", "source_document_id": 2064, "source_title": "Strategies for In Vivo Screening and Mitigation of Hepatotoxicity Associated with Antisense Drugs.", "pmid": "28918038", "source_pmcid": "PMC5537172", "doi": "10.1016/j.omtn.2017.07.003", "source_url": "https://pubmed.ncbi.nlm.nih.gov/28918038/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Furthermore, to study the underlying mechanisms of liver toxicity, we applied transcriptome profiling and pathway analyses and show that adverse in vivo liver phenotypes correlate with the number of potent, hybridization-mediated off-target effects (OTEs).", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "hepatotoxicity, liver, transcriptome, seq, offtarget", "record": "offtarget:66" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 67, "canonical_name": "LNA ASO", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hybridization/mismatch off-target effect", "evidence_label": "hybridization/mismatch off-target effect", "evidence_grade": "A", "source_location": "RESULTS > Hepatotoxicity of LNA ASOs is RNase H1 dependent; paragraph 35", "source_document_id": 2062, "source_title": "Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts.", "pmid": "26553810", "source_pmcid": "PMC4797265", "doi": "10.1093/nar/gkv1210", "source_url": "https://pubmed.ncbi.nlm.nih.gov/26553810/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "We observed highly selective transcript knockdown in mice treated with non-hepatotoxic LNA ASOs, while the levels of many unintended transcripts were reduced in mice treated with hepatotoxic LNA ASOs.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "hepatotoxicity, rna, offtarget, mismatch, hybridization", "record": "offtarget:67" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 8, "canonical_name": "GalNAc-siRNA panel from PMID 29459660", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "A", "source_location": "Results > siRNA off-targets are enriched for seed complementarity; paragraph 17", "source_document_id": 2058, "source_title": "Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.", "pmid": "29459660", "source_pmcid": "PMC5818625", "doi": "10.1038/s41467-018-02989-4", "source_url": "https://pubmed.ncbi.nlm.nih.gov/29459660/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Consistent with these data, global transcriptome profiling by RNAseq shows RISC loading-dependent downregulation of RNAs enriched for a seed match to the antisense but not the sense strand of GalNAc-siRNAs.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "galnac, hepatotoxicity, seed, seed-mediated, offtarget", "record": "offtarget:8" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 48, "canonical_name": "HsPCSK9-1811-LNA/GalNAc ASO panel from PMID 34760338", "modality": "ASO", "target_gene_symbol": "PCSK9", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "renal; hepatic", "evidence_label": "renal and hepatic safety", "evidence_grade": "A", "source_location": "Results > Evaluating the safety of the GalNAc conjugate in rat; paragraph 15", "source_document_id": 1632, "source_title": "Drug discovery and development scheme for liver-targeting bridged nucleic acid antisense oligonucleotides.", "pmid": "34760338", "source_pmcid": "PMC8560717", "doi": "10.1016/j.omtn.2021.10.008", "source_url": "https://pubmed.ncbi.nlm.nih.gov/34760338/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Histopathological examination revealed mild injury with degeneration, karyomegaly, single-cell necrosis, and vacuolation in proximal tubules in both animals dosed at 30 mg/kg.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 7, "triage_matched_terms": "pcsk9, galnac, hepatic, liver", "record": "toxicity:48" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 556, "canonical_name": "siPCSK9 (recovered B2 from PMID:41290746, curator:CM)", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "unspecified", "modification_annotation_status": "unspecified", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "A", "source_location": "Results > NP containing PCSK9 siRNA and STING agonists enable safe and effective cancer immunotherapy; paragraph 17", "source_document_id": 7717, "source_title": "Silencing PCSK9 reshapes the spatiotemporal activation of STING for safe and effective cancer immunotherapy.", "pmid": "41290746", "source_pmcid": "PMC12749358", "doi": "10.1038/s41467-025-66630-x", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41290746/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "exhibited excellent safety profiles, without body weight changes at 24 h and 48 h post-administration", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "pcsk9, hepatic, hepatotoxicity", "record": "toxicity:556" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 331, "canonical_name": "F7-1 siRNA", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "B", "source_location": "Results > Enrichment analysis of seed region matches in F7-1 off-target genes; paragraph 13", "source_document_id": 15845, "source_title": "Single base mismatches in the mRNA target site allow specific seed region-mediated off-target binding of siRNA targeting human coagulation factor 7.", "pmid": "22258146", "source_pmcid": "PMC3342946", "doi": "10.4161/rna.9.1.18121", "source_url": "https://pubmed.ncbi.nlm.nih.gov/22258146/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Accept B: PubMed abstract gives a direct abstract-level signal for seed-mediated off-target effect in F7-1 siRNA; no full passage, so curator kept confidence limited.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "human, seed, seed-mediated, seed region, offtarget, mismatch", "record": "offtarget:331" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 333, "canonical_name": "ATXN3-AON", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hybridization/mismatch off-target effect", "evidence_label": "hybridization/mismatch off-target effect", "evidence_grade": "B", "source_location": "Results > Hybridization-dependent off-target splicing events do not play a major role after transfection; paragraph 19", "source_document_id": 1442, "source_title": "Determining off-target effects of splice-switching antisense oligonucleotides using short read RNAseq in neuronally differentiated human induced pluripotent stem cells.", "pmid": "41066632", "source_pmcid": "PMC12581821", "doi": "10.1093/hmg/ddaf153", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41066632/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "In this study, we used three different splice-switching AONs targeting three different human transcripts to study their transcriptome-wide, hybridization-dependent off-target effects with short read RNAseq.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "human, rna, seq, offtarget, mismatch, hybridization", "record": "offtarget:333" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 338, "canonical_name": "siCD46 siRNA", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hybridization/mismatch off-target effect", "evidence_label": "hybridization/mismatch off-target effect", "evidence_grade": "B", "source_location": "RESULTS > Comparison of site-specific alterations in siRNA or target sequence; paragraph 15", "source_document_id": 15336, "source_title": "Analysis of siRNA specificity on targets with double-nucleotide mismatches.", "pmid": "18420656", "source_pmcid": "PMC2396434", "doi": "10.1093/nar/gkn190", "source_url": "https://pubmed.ncbi.nlm.nih.gov/18420656/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Accept C: PubMed abstract gives a weak abstract-level signal for hybridization/mismatch off-target effect in siCD46 siRNA; no full passage, so curator kept confidence limited.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "alt, rna, seq, offtarget, mismatch, hybridization", "record": "offtarget:338" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 345, "canonical_name": "siRNA-5", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "B", "source_location": "Results > siRNA off-targets are enriched for seed complementarity; paragraph 17", "source_document_id": 2058, "source_title": "Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.", "pmid": "29459660", "source_pmcid": "PMC5818625", "doi": "10.1038/s41467-018-02989-4", "source_url": "https://pubmed.ncbi.nlm.nih.gov/29459660/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Consistent with these data, global transcriptome profiling by RNAseq shows RISC loading-dependent downregulation of RNAs enriched for a seed match to the antisense but not the sense strand of GalNAc-siRNAs.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "galnac, hepatotoxicity, seed, seed-mediated, offtarget", "record": "offtarget:345" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 392, "canonical_name": "LNA ASO", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hybridization/mismatch off-target effect", "evidence_label": "hybridization/mismatch off-target effect", "evidence_grade": "B", "source_location": "RESULTS > Hepatotoxicity of LNA ASOs is RNase H1 dependent; paragraph 35", "source_document_id": 2062, "source_title": "Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts.", "pmid": "26553810", "source_pmcid": "PMC4797265", "doi": "10.1093/nar/gkv1210", "source_url": "https://pubmed.ncbi.nlm.nih.gov/26553810/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "We observed highly selective transcript knockdown in mice treated with non-hepatotoxic LNA ASOs, while the levels of many unintended transcripts were reduced in mice treated with hepatotoxic LNA ASOs.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "hepatotoxicity, rna, offtarget, mismatch, hybridization", "record": "offtarget:392" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 42, "canonical_name": "TNRC6; GW182; AGO2", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "B", "source_location": "PubMed abstract", "source_document_id": 1011, "source_title": "Mechanistic Insights into Hybridization-Based Off-Target Activity of GalNAc-siRNA Conjugates.", "pmid": "40134378", "source_pmcid": null, "doi": "10.1089/nat.2024.0090", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40134378/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-linked derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "We demonstrate that knocking down AGO2, but not AGO1 or AGO4, is protective against GalNAc-siRNA-driven off-target activity and hepatotoxicity.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "galnac, seed, seed-mediated, offtarget, hybridization", "record": "offtarget:42" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 462, "canonical_name": "si098-DV29P", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "seed-mediated off-target effect", "evidence_label": "seed-mediated off-target effect", "evidence_grade": "B", "source_location": "Results > In vivo silencing of AGT by GalNAc-siRNAs; paragraph 13", "source_document_id": 1477, "source_title": "Design, pharmacology, and toxicology of a novel chemically modified siRNA targeting hepatic angiotensinogen.", "pmid": "40385635", "source_pmcid": "PMC12083919", "doi": "10.1016/j.omtn.2025.102542", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40385635/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "However, two siRNAs, si098-DV29P and si086-DV26P, exerted relatively strong inhibition on their potential off-target genes (Figures S10B and S10E), suggesting that measures should be taken to prevent and control the off-target risk.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "galnac, hepatic, seed, seed-mediated, offtarget", "record": "offtarget:462" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 47, "canonical_name": "unspecified antisense oligonucleotide", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "transcriptome-level off-target effect", "evidence_label": "transcriptome-level off-target effect", "evidence_grade": "B", "source_location": "PubMed abstract", "source_document_id": 2216, "source_title": "Using RNA-seq to Assess Off-Target Effects of Antisense Oligonucleotides in Human Cell Lines.", "pmid": "33314011", "source_pmcid": null, "doi": "10.1007/s40291-020-00504-4", "source_url": "https://pubmed.ncbi.nlm.nih.gov/33314011/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-linked derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "METHODS: We extend recent studies by investigating the off-target profile of two 17-mer antisense oligonucleotides in two distinct human cell lines by a whole-transcriptome study using RNA sequencing.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "human, transcriptome, rna-seq, rna, seq, offtarget", "record": "offtarget:47" }, { "evidence_domain": "offtarget", "entity_table": "offtarget_evidence", "evidence_id": 534, "canonical_name": "89E-06", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hybridization/mismatch off-target effect", "evidence_label": "hybridization/mismatch off-target effect", "evidence_grade": "B", "source_location": "Results > High Confirmation Rate of In Silico Predicted OTEs in Mouse Liver; paragraph 14", "source_document_id": 2064, "source_title": "Strategies for In Vivo Screening and Mitigation of Hepatotoxicity Associated with Antisense Drugs.", "pmid": "28918038", "source_pmcid": "PMC5537172", "doi": "10.1016/j.omtn.2017.07.003", "source_url": "https://pubmed.ncbi.nlm.nih.gov/28918038/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Our data show that liver toxicity of LNA-containing gapmer ASOs is associated with their ability to hybridize to off-target transcripts and downregulate their expression.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 5, "triage_matched_terms": "hepatotoxicity, liver, offtarget, mismatch, hybridization", "record": "offtarget:534" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 359, "canonical_name": "PCSK9; NCT04652726; inclisiran", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "B", "source_location": "PubMed abstract", "source_document_id": 1155, "source_title": "Efficacy and safety of inclisiran in adolescents with heterozygous familial hypercholesterolaemia (ORION-16): a two-part, randomised, multicentre clinical trial.", "pmid": "41616799", "source_pmcid": null, "doi": "10.1016/S2213-8587(25)00351-1", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41616799/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-linked derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Inclisiran was well tolerated, with a safety profile comparable to studies in adults.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "pcsk9, hepatic, hepatotoxicity", "record": "toxicity:359" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 361, "canonical_name": "PCSK9; inclisiran", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "B", "source_location": "PubMed abstract", "source_document_id": 1179, "source_title": "Comparative effectiveness and safety of inclisiran versus evolocumab and alirocumab: a 180-day real-world study.", "pmid": "42141407", "source_pmcid": null, "doi": "10.1186/s12872-026-05931-5", "source_url": "https://pubmed.ncbi.nlm.nih.gov/42141407/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-linked derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "All therapies were well-tolerated with no new safety signals.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "pcsk9, hepatic, hepatotoxicity", "record": "toxicity:361" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 382, "canonical_name": "PCSK9; NCT05763875; Inclisiran", "modality": "ASO/siRNA mixed context", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "B", "source_location": "PubMed abstract", "source_document_id": 2280, "source_title": "Safety and Lipid-Lowering Efficacy of Inclisiran Monotherapy in Patients Without ASCVD: The VICTORION-Mono Randomized Clinical Trial.", "pmid": "40392667", "source_pmcid": null, "doi": "10.1016/j.jacc.2025.04.049", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40392667/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-linked derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Inclisiran was well tolerated, with no new safety concerns.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "pcsk9, hepatic, hepatotoxicity", "record": "toxicity:382" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 401, "canonical_name": "PCSK9; NCT03060577; inclisiran", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "B", "source_location": "PubMed abstract", "source_document_id": 2697, "source_title": "Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3): results from the 4-year open-label extension of the ORION-1 trial.", "pmid": "36620965", "source_pmcid": null, "doi": "10.1016/S2213-8587(22)00353-9", "source_url": "https://pubmed.ncbi.nlm.nih.gov/36620965/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-linked derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Adverse events at the injection site were reported in 39 (14%) of 284 patients in the inclisiran-only arm and 12 (14%) of 87 patients in the switching arm.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "pcsk9, hepatic, hepatotoxicity", "record": "toxicity:401" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 245, "canonical_name": "SPC5001", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "C", "source_location": "PubMed abstract", "source_document_id": 1029, "source_title": "Predicting nucleic acid drug-induced nephrotoxicity using a 3D human renal proximal tubule spheroid model.", "pmid": "41500580", "source_pmcid": null, "doi": "10.2131/jts.51.75", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41500580/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-linked derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Significant ATP depletion was observed only after prolonged exposure to SPC5001, a nephrotoxic antisense oligonucleotide.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "hepatic, hepatotoxicity, human, renal, nephrotoxicity, nephrotoxic", "record": "toxicity:245" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 313, "canonical_name": "PCSK9; GN3; MC3-LNP", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "C", "source_location": "PubMed abstract", "source_document_id": 11712, "source_title": "Engineering a biomimetic system for hepatocyte-specific RNAi treatment of non-alcoholic fatty liver disease.", "pmid": "37951519", "source_pmcid": null, "doi": "10.1016/j.actbio.2023.10.038", "source_url": "https://pubmed.ncbi.nlm.nih.gov/37951519/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-linked derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Having optimized the GalNAc-engineering strategy, insertion orders, and cell membrane source, we obtained the best-performing GalNAc-formulations allowing strong hepatocyte-specific internalization with reduced Kupffer cell capture, resulting in robust gene silencing and less hepatotoxicity when compared with cationic lipid-based GalNAc-formulations.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 8, "triage_matched_terms": "pcsk9, hepatic, hepatotoxicity, liver, hepatocyte", "record": "toxicity:313" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 420, "canonical_name": "G5-GalNAc siRNA platform", "modality": "siRNA", "target_gene_symbol": "PCSK9/AGT", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "general safety", "evidence_label": "nonclinical toxicology and biodistribution safety", "evidence_grade": "C", "source_location": "Discussion; paragraph 17", "source_document_id": 1069, "source_title": "Ribofuranose-based GalNAc-conjugated siRNA enhances the liver-targeted delivery and elicits robust RNAi-mediated gene silencing.", "pmid": "41541269", "source_pmcid": "PMC12800395", "doi": "10.1016/j.omtn.2025.102801", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41541269/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "The no observed adverse effect level was established at 300 mg/kg.", "audited_at": "2026-06-07T02:20:35+00:00", "triage_match_score": 6, "triage_matched_terms": "pcsk9, galnac, liver", "record": "toxicity:420" } ], "candidate_gap_records": [ { "id": 16930, "queue_id": 46099, "pmid": "22258146", "doi": "10.4161/rna.9.1.18121", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed title", "matched_terms": "off-target;seed;mismatch", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=off-target, seed, mismatch; source title: Single base mismatches in the mRNA target site allow specific seed region-mediated off-target binding of siRNA targeting human coagulation factor 7.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Single base mismatches in the mRNA target site allow specific seed region-mediated off-target binding of siRNA targeting human coagulation factor 7.", "triage_match_score": 5, "triage_matched_terms": "human, seed, seed region, offtarget, mismatch" }, { "id": 32407, "queue_id": 61576, "pmid": "11687950", "doi": "10.1038/sj.neo.7900185", "evidence_domain": "offtarget", "candidate_modality": "ASO", "source_location": "PubMed title", "matched_terms": "microarray", "candidate_signal": "offtarget candidate; derived PubMed query=aso_oligo_offtarget; terms=microarray; source title: Genome-wide screening of genes showing altered expression in liver metastases of human colorectal cancers by cDNA microarray.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Genome-wide screening of genes showing altered expression in liver metastases of human colorectal cancers by cDNA microarray.", "triage_match_score": 5, "triage_matched_terms": "liver, alt, ast, human, offtarget" }, { "id": 16768, "queue_id": 45937, "pmid": "27308945", "doi": "10.1089/scd.2015.0383", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed query-level off-target/specificity candidate; exact source location requires curator check", "matched_terms": "sirna;rnai;off-target", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=sirna, rnai, off-target; source title: Modeling Nonalcoholic Fatty Liver Disease with Human Pluripotent Stem Cell-Derived Immature Hepatocyte-Like Cells Reveals Activation of PLIN2 and Confirms Regulatory Functions of Peroxisome Proliferator-Activated Receptor Alpha.", "suggested_evidence_grade": "C", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Modeling Nonalcoholic Fatty Liver Disease with Human Pluripotent Stem Cell-Derived Immature Hepatocyte-Like Cells Reveals Activation of PLIN2 and Confirms Regulatory Functions of Peroxisome Proliferator-Activated Receptor Alpha.", "triage_match_score": 4, "triage_matched_terms": "liver, hepatocyte, human, offtarget" }, { "id": 17756, "queue_id": 46925, "pmid": "36006421", "doi": "10.18632/aging.204242", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed query-level off-target/specificity candidate; exact source location requires curator check", "matched_terms": "sirna;rnai;off-target", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=sirna, rnai, off-target; source title: Gene expression profile of human colorectal cancer identified NKTR as a biomarker for liver metastasis.", "suggested_evidence_grade": "C", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Gene expression profile of human colorectal cancer identified NKTR as a biomarker for liver metastasis.", "triage_match_score": 4, "triage_matched_terms": "liver, ast, human, offtarget" }, { "id": 17844, "queue_id": 47013, "pmid": "18646787", "doi": "10.1021/pr800153s", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed query-level off-target/specificity candidate; exact source location requires curator check", "matched_terms": "sirna;rnai;off-target", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=sirna, rnai, off-target; source title: Quantitative proteomic signature of liver cancer cells: tissue transglutaminase 2 could be a novel protein candidate of human hepatocellular carcinoma.", "suggested_evidence_grade": "C", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Quantitative proteomic signature of liver cancer cells: tissue transglutaminase 2 could be a novel protein candidate of human hepatocellular carcinoma.", "triage_match_score": 4, "triage_matched_terms": "liver, hepatocellular, human, offtarget" }, { "id": 17855, "queue_id": 47024, "pmid": "15940635", "doi": "10.1053/j.gastro.2005.03.001", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed query-level off-target/specificity candidate; exact source location requires curator check", "matched_terms": "sirna;rnai;off-target", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=sirna, rnai, off-target; source title: Use of adenovirus-delivered siRNA to target oncoprotein p28GANK in hepatocellular carcinoma.", "suggested_evidence_grade": "C", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Use of adenovirus-delivered siRNA to target oncoprotein p28GANK in hepatocellular carcinoma.", "triage_match_score": 4, "triage_matched_terms": "liver, hepatocellular, ast, offtarget" }, { "id": 19573, "queue_id": 48742, "pmid": "29783070", "doi": "10.1016/j.gene.2018.05.042", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed query-level off-target/specificity candidate; exact source location requires curator check", "matched_terms": "sirna;rnai;off-target", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=sirna, rnai, off-target; source title: CDH17 alters MMP-2 expression via canonical NF-κB signalling in human gastric cancer.", "suggested_evidence_grade": "C", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "CDH17 alters MMP-2 expression via canonical NF-κB signalling in human gastric cancer.", "triage_match_score": 4, "triage_matched_terms": "alt, ast, human, offtarget" }, { "id": 20181, "queue_id": 49350, "pmid": "18360908", "doi": "10.1002/jmv.21164", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed query-level off-target/specificity candidate; exact source location requires curator check", "matched_terms": "sirna;rnai;off-target", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=sirna, rnai, off-target; source title: Inhibition of West Nile Virus replication by retrovirus-delivered small interfering RNA in human neuroblastoma cells.", "suggested_evidence_grade": "C", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Inhibition of West Nile Virus replication by retrovirus-delivered small interfering RNA in human neuroblastoma cells.", "triage_match_score": 4, "triage_matched_terms": "liver, ast, human, offtarget" }, { "id": 8209, "queue_id": 28349, "pmid": "38887517", "doi": "10.3389/fcell.2024.1416780", "evidence_domain": "offtarget", "candidate_modality": "ASO/siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "offtarget candidate from queue only; source title: Integrating scRNA-seq and bulk RNA-seq to explore the differentiation mechanism of human nail stem cells mediated by onychofibroblasts.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Integrating scRNA-seq and bulk RNA-seq to explore the differentiation mechanism of human nail stem cells mediated by onychofibroblasts.", "triage_match_score": 6, "triage_matched_terms": "ast, human, rna-seq, rna, seq, offtarget" }, { "id": 1028, "queue_id": 2430, "pmid": "39045328", "doi": "10.3389/fgene.2024.1397502", "evidence_domain": "offtarget", "candidate_modality": "ASO/siRNA", "source_location": "PubMed title", "matched_terms": "transcriptome", "candidate_signal": "offtarget candidate; matched derived terms: transcriptome; source title: Alternative splicing responses to salt stress in Glycyrrhiza uralensis revealed by global profiling of transcriptome RNA-seq datasets.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Alternative splicing responses to salt stress in Glycyrrhiza uralensis revealed by global profiling of transcriptome RNA-seq datasets.", "triage_match_score": 6, "triage_matched_terms": "alt, transcriptome, rna-seq, rna, seq, offtarget" }, { "id": 1030, "queue_id": 2434, "pmid": "38966147", "doi": "10.3389/fpls.2024.1394223", "evidence_domain": "offtarget", "candidate_modality": "ASO/siRNA", "source_location": "PubMed abstract sentence 4", "matched_terms": "transcriptome", "candidate_signal": "offtarget candidate; matched derived terms: transcriptome; source title: RNA-seq analysis reveals transcriptome reprogramming and alternative splicing during early response to salt stress in tomato root.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "RNA-seq analysis reveals transcriptome reprogramming and alternative splicing during early response to salt stress in tomato root.", "triage_match_score": 6, "triage_matched_terms": "alt, transcriptome, rna-seq, rna, seq, offtarget" }, { "id": 15221, "queue_id": 44390, "pmid": "38958110", "doi": "10.1002/adma.202404784", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed abstract sentence 7", "matched_terms": "transcriptome", "candidate_signal": "offtarget candidate; matched derived terms: transcriptome; source title: Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.", "triage_match_score": 6, "triage_matched_terms": "liver, hepatocellular, ast, transcriptome, rna, offtarget" }, { "id": 18034, "queue_id": 47203, "pmid": "31408249", "doi": "10.1002/jgm.3117", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed title", "matched_terms": "rna-seq;mirna", "candidate_signal": "offtarget candidate; derived PubMed query=sirna_rnai_offtarget; terms=rna-seq, mirna; source title: Identification of human miR-1839-5p by small RNA-seq, a miRNA enriched in neoplastic tissues.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Identification of human miR-1839-5p by small RNA-seq, a miRNA enriched in neoplastic tissues.", "triage_match_score": 6, "triage_matched_terms": "ast, human, rna-seq, rna, seq, offtarget" }, { "id": 26899, "queue_id": 56068, "pmid": "30476925", "doi": "10.1159/000495483", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed title", "matched_terms": "rna-seq;microarray;silencing", "candidate_signal": "offtarget candidate; derived PubMed query=rnai_screen_specificity; terms=rna-seq, microarray, silencing; source title: The Clinicopathological Significance and Correlative Signaling Pathways of an Autophagy-Related Gene, Ambra1, in Breast Cancer: a Study of 25 Microarray RNA-Seq Datasets and in-House Gene Silencing.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "The Clinicopathological Significance and Correlative Signaling Pathways of an Autophagy-Related Gene, Ambra1, in Breast Cancer: a Study of 25 Microarray RNA-Seq Datasets and in-House Gene Silencing.", "triage_match_score": 6, "triage_matched_terms": "ast, rna-seq, rna, seq, microarray, offtarget" }, { "id": 28335, "queue_id": 57504, "pmid": "31645899", "doi": "10.18632/oncotarget.27208", "evidence_domain": "offtarget", "candidate_modality": "siRNA", "source_location": "PubMed title", "matched_terms": "transcriptome;rna-seq;silencing", "candidate_signal": "offtarget candidate; derived PubMed query=rnai_screen_specificity; terms=transcriptome, rna-seq, silencing; source title: New prognostic markers revealed by RNA-Seq transcriptome analysis after MYC silencing in a metastatic gastric cancer cell line.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "New prognostic markers revealed by RNA-Seq transcriptome analysis after MYC silencing in a metastatic gastric cancer cell line.", "triage_match_score": 6, "triage_matched_terms": "ast, transcriptome, rna-seq, rna, seq, offtarget" }, { "id": 178, "queue_id": 388, "pmid": "38742636", "doi": "10.1093/nar/gkae350", "evidence_domain": "toxicity", "candidate_modality": "siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Evaluating the oral delivery of GalNAc-conjugated siRNAs in rodents and non-human primates.", "triage_match_score": 3, "triage_matched_terms": "galnac, liver, human" }, { "id": 1897, "queue_id": 4523, "pmid": "33928571", "doi": "10.1007/978-1-0716-1298-9_6", "evidence_domain": "toxicity", "candidate_modality": "siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: siRNA Design and GalNAc-Empowered Hepatic Targeted Delivery.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "siRNA Design and GalNAc-Empowered Hepatic Targeted Delivery.", "triage_match_score": 3, "triage_matched_terms": "galnac, hepatic, liver" }, { "id": 3380, "queue_id": 8202, "pmid": "41430089", "doi": "10.1038/s41598-025-32407-x", "evidence_domain": "toxicity", "candidate_modality": "ASO/siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Delivery of lipid nanoparticles containing small interfering RNA targeting transmembrane serine protease 4 in a human gastric cancer model using nude mice.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Delivery of lipid nanoparticles containing small interfering RNA targeting transmembrane serine protease 4 in a human gastric cancer model using nude mice.", "triage_match_score": 3, "triage_matched_terms": "liver, ast, human" }, { "id": 3745, "queue_id": 9077, "pmid": "40454419", "doi": "10.1016/j.omtm.2025.101470", "evidence_domain": "toxicity", "candidate_modality": "ASO/siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Serum factors create species-specific barriers to hepatic gene transfer by lipid nanoparticles in liver-humanized mice.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Serum factors create species-specific barriers to hepatic gene transfer by lipid nanoparticles in liver-humanized mice.", "triage_match_score": 3, "triage_matched_terms": "hepatic, liver, human" }, { "id": 4319, "queue_id": 10479, "pmid": "35671983", "doi": "10.1016/j.nano.2022.102572", "evidence_domain": "toxicity", "candidate_modality": "siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Stealth oxime ether lipid vesicles promote delivery of functional DsiRNA in human lung cancer A549 tumor bearing mouse xenografts.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Stealth oxime ether lipid vesicles promote delivery of functional DsiRNA in human lung cancer A549 tumor bearing mouse xenografts.", "triage_match_score": 3, "triage_matched_terms": "liver, alt, human" }, { "id": 5499, "queue_id": 16125, "pmid": "41688832", "doi": "10.1245/s10434-026-19135-w", "evidence_domain": "toxicity", "candidate_modality": "ASO", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: ASO Visual Abstract: Oncological Adequacy of R1 Vascular Margin in Minimally Invasive Liver Surgery for Hepatocellular Carcinoma and Colorectal Liver Metastases: A Meta-analysis.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "ASO Visual Abstract: Oncological Adequacy of R1 Vascular Margin in Minimally Invasive Liver Surgery for Hepatocellular Carcinoma and Colorectal Liver Metastases: A Meta-analysis.", "triage_match_score": 3, "triage_matched_terms": "liver, hepatocellular, ast" }, { "id": 6142, "queue_id": 19244, "pmid": "41398432", "doi": "10.1038/s41598-025-32555-0", "evidence_domain": "toxicity", "candidate_modality": "ASO/siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: A dual-functional cobalt ferrite nanocomplex for targeted cisplatin prodrug delivery and MALAT1 gene silencing in gastric cancer cells.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "A dual-functional cobalt ferrite nanocomplex for targeted cisplatin prodrug delivery and MALAT1 gene silencing in gastric cancer cells.", "triage_match_score": 3, "triage_matched_terms": "liver, alt, ast" }, { "id": 6307, "queue_id": 19939, "pmid": "41237431", "doi": "10.1016/j.clinsp.2025.100839", "evidence_domain": "toxicity", "candidate_modality": "ASO/siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Effects of pemafibrate (a selective PPAR-α agonist) versus weight loss through an intensive lifestyle modification on liver enzymes, serum soluble dipeptidyl peptidase-4, and hepatic steatosis and fibrosis evaluated by FibroScan transient elastography in people with type 2 diabetes and MASLD.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Effects of pemafibrate (a selective PPAR-α agonist) versus weight loss through an intensive lifestyle modification on liver enzymes, serum soluble dipeptidyl peptidase-4, and hepatic steatosis and fibrosis evaluated by FibroScan transient elastography in people with type 2 diabetes and MASLD.", "triage_match_score": 3, "triage_matched_terms": "hepatic, liver, ast" }, { "id": 6953, "queue_id": 22879, "pmid": "40669774", "doi": "10.1016/j.taap.2025.117465", "evidence_domain": "toxicity", "candidate_modality": "ASO/siRNA", "source_location": "PubMed abstract sentence 11", "matched_terms": "renal", "candidate_signal": "toxicity candidate; matched derived terms: renal; source title: Hepatocyte mitochondrial DNA activated store-operated Ca(2+) entry via Stim1/Orai1-induced podocyte injury in trichloroethylene sensitized mice: A new insight in liver and kidney crosstalk.", "suggested_evidence_grade": "B", "confidence_label": "medium_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Hepatocyte mitochondrial DNA activated store-operated Ca(2+) entry via Stim1/Orai1-induced podocyte injury in trichloroethylene sensitized mice: A new insight in liver and kidney crosstalk.", "triage_match_score": 4, "triage_matched_terms": "liver, hepatocyte, renal, kidney" }, { "id": 1508, "queue_id": 3668, "pmid": "39417036", "doi": "10.1093/toxres/tfae173", "evidence_domain": "toxicity", "candidate_modality": "ASO/siRNA", "source_location": "PubMed abstract sentence 9", "matched_terms": "risk;adverse;renal", "candidate_signal": "toxicity candidate; matched derived terms: risk, adverse, renal; source title: 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) exposure induces hepatotoxicity and nephrotoxicity - role of oxidative stress, mitochondrial dysfunction and pathways of cytotoxicity.", "suggested_evidence_grade": "B", "confidence_label": "high_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) exposure induces hepatotoxicity and nephrotoxicity - role of oxidative stress, mitochondrial dysfunction and pathways of cytotoxicity.", "triage_match_score": 4, "triage_matched_terms": "hepatotoxicity, renal, nephrotoxicity, nephrotoxic" }, { "id": 8790, "queue_id": 30946, "pmid": "39460726", "doi": "10.1021/acsami.4c10171", "evidence_domain": "toxicity", "candidate_modality": "siRNA", "source_location": "PubMed abstract sentence 2", "matched_terms": "toxicity;toxic;renal", "candidate_signal": "toxicity candidate; matched derived terms: toxicity, toxic, renal; source title: Mitigation of Cisplatin-Induced Nephrotoxicity and Augmentation of Anticancer Potency via Tea Polyphenol Nanoparticles' Codelivery of siRNA from CRISPR/Cas9 Screened Targets.", "suggested_evidence_grade": "B", "confidence_label": "high_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Mitigation of Cisplatin-Induced Nephrotoxicity and Augmentation of Anticancer Potency via Tea Polyphenol Nanoparticles' Codelivery of siRNA from CRISPR/Cas9 Screened Targets.", "triage_match_score": 4, "triage_matched_terms": "liver, renal, nephrotoxicity, nephrotoxic" }, { "id": 2224, "queue_id": 5268, "pmid": "40080657", "doi": "10.1021/acschembio.5c00039", "evidence_domain": "toxicity", "candidate_modality": "siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Optimizing Peptide-Conjugated Lipid Nanoparticles for Efficient siRNA Delivery across the Blood-Brain Barrier and Treatment of Glioblastoma Multiforme.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Optimizing Peptide-Conjugated Lipid Nanoparticles for Efficient siRNA Delivery across the Blood-Brain Barrier and Treatment of Glioblastoma Multiforme.", "triage_match_score": 3, "triage_matched_terms": "liver, ast, blood" }, { "id": 3665, "queue_id": 8893, "pmid": "40633772", "doi": "10.1016/j.jconrel.2025.114018", "evidence_domain": "toxicity", "candidate_modality": "ASO", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Low-frequency ultrasound-mediated blood-brain barrier opening enables non-invasive lipid nanoparticle RNA delivery to glioblastoma.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Low-frequency ultrasound-mediated blood-brain barrier opening enables non-invasive lipid nanoparticle RNA delivery to glioblastoma.", "triage_match_score": 3, "triage_matched_terms": "liver, ast, blood" }, { "id": 9923, "queue_id": 34701, "pmid": "39963241", "doi": "10.3389/fphar.2025.1528250", "evidence_domain": "toxicity", "candidate_modality": "ASO/siRNA", "source_location": "source title", "matched_terms": null, "candidate_signal": "toxicity candidate from queue only; source title: Conditional knockdown of hepatic PCSK9 ameliorates high-fat diet-induced liver inflammation in mice.", "suggested_evidence_grade": "B", "confidence_label": "low_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Conditional knockdown of hepatic PCSK9 ameliorates high-fat diet-induced liver inflammation in mice.", "triage_match_score": 4, "triage_matched_terms": "pcsk9, hepatic, liver, inflammation" }, { "id": 1342, "queue_id": 3220, "pmid": "37772637", "doi": "10.1002/adhm.202301687", "evidence_domain": "toxicity", "candidate_modality": "ASO/siRNA", "source_location": "PubMed abstract sentence 5", "matched_terms": "toxicity;toxic", "candidate_signal": "toxicity candidate; matched derived terms: toxicity, toxic; source title: Lipid Nanoparticle Delivery Alters the Adjuvanticity of the TLR9 Agonist CpG by Innate Immune Activation in Lymphoid Tissue.", "suggested_evidence_grade": "B", "confidence_label": "high_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "redistribution_level": "derived_annotations_only", "source_title": "Lipid Nanoparticle Delivery Alters the Adjuvanticity of the TLR9 Agonist CpG by Innate Immune Activation in Lymphoid Tissue.", "triage_match_score": 4, "triage_matched_terms": "liver, alt, immune, tlr" } ], "modification_profiles": [ { "term": "galnac", "label": "GalNAc conjugation", "kind": "targeted conjugate", "synonyms": [ "galnac", "n-acetylgalactosamine" ], "release_records": 33, "candidate_records": 307, "benchmark_records": 16, "domain_counts": [ { "domain": "offtarget", "n": 8 }, { "domain": "toxicity", "n": 25 } ], "grade_counts": [ { "grade": "A", "n": 10 }, { "grade": "B", "n": 15 }, { "grade": "C", "n": 8 } ], "example_release_records": [ { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 16, "canonical_name": "JNJ-3989/JNJ-73763989 GalNAc-siRNA regimen from PMID 40919077", "modality": "siRNA", "target_gene_symbol": "HBV", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "general safety", "evidence_label": "safety/tolerability", "evidence_grade": "B", "source_location": "Results > Safety; paragraph 22", "source_document_id": 3517, "source_title": "Peginterferon-alpha-2a add-on to treatment with siRNA JNJ-73763989 in virologically suppressed chronic hepatitis B: The phase II PENGUIN study.", "pmid": "40919077", "source_pmcid": "PMC12409438", "doi": "10.1016/j.jhepr.2025.101516", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40919077/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Safety and tolerability of study drugs and procedures were evaluated via assessments of adverse events (AEs), including serious AEs (SAEs), physical examination, and laboratory abnormalities, including changes in ALT throughout the study.", "audited_at": "2026-06-07T02:20:35+00:00" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 40, "canonical_name": "ESC+ GalNAc-siRNA D1/D4/D6/D9 panel from PMID 35736224", "modality": "siRNA", "target_gene_symbol": "TTR; HAO1", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "A", "source_location": "RESULTS > GNA improves the therapeutic index in rats; paragraph 33", "source_document_id": 1411, "source_title": "From bench to bedside: Improving the clinical safety of GalNAc-siRNA conjugates using seed-pairing destabilization.", "pmid": "35736224", "source_pmcid": "PMC9262600", "doi": "10.1093/nar/gkac539", "source_url": "https://pubmed.ncbi.nlm.nih.gov/35736224/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "The increased levels of ALT, AST and GLDH observed in animals treated with the parent D1 were completely normalized with D16, which closely mimicked that of the saline control (Figure 4D).", "audited_at": "2026-06-07T02:20:35+00:00" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 45, "canonical_name": "GalNAc-G-quadruplex oligonucleotide panel from PMID 35745067", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "general safety", "evidence_label": "cytotoxicity", "evidence_grade": "C", "source_location": "2. Results > 2.4. Toxicity Assays; paragraph 17", "source_document_id": 4073, "source_title": "Properties of Parallel Tetramolecular G-Quadruplex Carrying N-Acetylgalactosamine as Potential Enhancer for Oligonucleotide Delivery to Hepatocytes.", "pmid": "35745067", "source_pmcid": "PMC9228010", "doi": "10.3390/molecules27123944", "source_url": "https://pubmed.ncbi.nlm.nih.gov/35745067/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Prior the evaluation of internalization and antisense inhibition of luciferase, we evaluate the potential toxicity of GalNAc-oligonucleotides by using MTT assay at 60 nM, 120 nM and 300 nM oligonucleotide concentration after 24 h.", "audited_at": "2026-06-07T02:20:35+00:00" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 48, "canonical_name": "HsPCSK9-1811-LNA/GalNAc ASO panel from PMID 34760338", "modality": "ASO", "target_gene_symbol": "PCSK9", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "renal; hepatic", "evidence_label": "renal and hepatic safety", "evidence_grade": "A", "source_location": "Results > Evaluating the safety of the GalNAc conjugate in rat; paragraph 15", "source_document_id": 1632, "source_title": "Drug discovery and development scheme for liver-targeting bridged nucleic acid antisense oligonucleotides.", "pmid": "34760338", "source_pmcid": "PMC8560717", "doi": "10.1016/j.omtn.2021.10.008", "source_url": "https://pubmed.ncbi.nlm.nih.gov/34760338/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Histopathological examination revealed mild injury with degeneration, karyomegaly, single-cell necrosis, and vacuolation in proximal tubules in both animals dosed at 30 mg/kg.", "audited_at": "2026-06-07T02:20:35+00:00" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 59, "canonical_name": "GalNAc AON-B/D/E panel from PMID 30583097", "modality": "ASO", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "renal", "evidence_label": "renal safety", "evidence_grade": "A", "source_location": "Results > GalNAc Conjugation Masked the In Vivo Nephrotoxicity Potential of AON Drug Candidates; paragraph 7", "source_document_id": 2059, "source_title": "GalNAc Conjugation Attenuates the Cytotoxicity of Antisense Oligonucleotide Drugs in Renal Tubular Cells.", "pmid": "30583097", "source_pmcid": "PMC6305803", "doi": "10.1016/j.omtn.2018.11.005", "source_url": "https://pubmed.ncbi.nlm.nih.gov/30583097/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "Indeed, mild histopathological abnormalities were observed in the renal cortex of one rat treated with GalNac AON-B in a 2-week study (Figure 2A).", "audited_at": "2026-06-07T02:20:35+00:00" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 60, "canonical_name": "GalNAc-siRNA hepatotoxicity panel with REVERSIR from PMID 29459660", "modality": "siRNA", "target_gene_symbol": "HAO1; TTR", "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "A", "source_location": "Results > Blocking siRNA-loaded RISC activity mitigates hepatotoxicity; paragraph 12", "source_document_id": 2058, "source_title": "Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.", "pmid": "29459660", "source_pmcid": "PMC5818625", "doi": "10.1038/s41467-018-02989-4", "source_url": "https://pubmed.ncbi.nlm.nih.gov/29459660/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "In the rat, hepatotoxic siRNAs (siRNA-1 shown here) had hepatocellular degeneration (bracketed area), increased sinusoidal cells due to Kupffer cell hyperplasia and/or leukocyte infiltration (#), single cell necrosis (*), increased mitoses (^), and hepatocellular vacuolation (arrow).", "audited_at": "2026-06-07T02:20:35+00:00" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 70, "canonical_name": "siRNA candidate from PMID 40692538", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hematologic", "evidence_label": "platelet/bleeding safety", "evidence_grade": "A", "source_location": "Results > Drugs-Loaded GalNac-RBC-EVs Were Non-Toxic to Mice; paragraph 42", "source_document_id": 1242, "source_title": "Protective Effects of GalNac-Modified Red Blood Cell-Derived Extracellular Vesicles Against Liver Diseases.", "pmid": "40692538", "source_pmcid": "PMC12277184", "doi": "10.2147/IJN.S510937", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40692538/", "source_license_status": "abstract_metadata_only", "source_reuse_category": "derived_annotations_only", "curation_basis": "source-localized derived annotation", "raw_quote_included": "false", "is_observed_experimental": 1, "is_computational_prediction": 0, "audit_validation_status": "curator_verified", "curator_decision": "accept", "curator_id": "ni_jie", "audit_note": "No significant toxicity was observed in vital organs (ALT/AST levels, P>0.05; histopathology scores, P>0.05).", "audited_at": "2026-06-07T02:20:35+00:00" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 117, "canonical_name": "siRNA candidate from PMID 41949334", "modality": "siRNA", "target_gene_symbol": null, "disease_context": null, "sense_sequence": null, "antisense_sequence": null, "guide_sequence": null, "passenger_sequence": null, "seed_region": null, "backbone_chemistry": null, "sugar_modification": null, "base_modification": null, "conjugate_delivery": null, "sequence_annotation_status": "needs_curator_sequence_curation", "modification_annotation_status": "needs_curator_modification_curation", "category": "hepatic", "evidence_label": "hepatotoxicity", "evidence_grade": "B", "source_location": "Results > Treatment of Hepatic Spheroids With Chemically Modified GalNAc‐Conjugated siRNA; 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