{ "version": "20260604_core_validation_v45", "dossier_id": "0af107408c52712a", "title": "OligoVigil Safety Evidence Dossier", "headline": "From oligonucleotide design to citable safety evidence.", "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": "" }, "executive_summary": { "interpretation": "Evidence-dense safety review required.", "supported_concerns": 7, "candidate_gap_concerns": 0, "release_records_considered": 25, "candidate_gap_records_considered": 36, "prediction_boundary": "no de novo safety prediction" }, "dossier_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": [ { 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"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 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"/api/prov_graph?sequence=AUGCUACUGACUGA&target=PCSK9&modification=GalNAc&delivery=GalNAc&endpoint=hepatic&species=human", "export_actions": [ { "label": "JSON dossier", "url": "/api/safety_dossier?sequence=AUGCUACUGACUGA&target=PCSK9&modification=GalNAc&delivery=GalNAc&endpoint=hepatic&species=human" }, { "label": "Evidence graph JSON", "url": "/api/evidence_graph?sequence=AUGCUACUGACUGA&target=PCSK9&modification=GalNAc&delivery=GalNAc&endpoint=hepatic&species=human" }, { "label": "W3C PROV profile", "url": "/api/prov_graph?sequence=AUGCUACUGACUGA&target=PCSK9&modification=GalNAc&delivery=GalNAc&endpoint=hepatic&species=human" }, { "label": "Print or save PDF", "url": "/#triage" } ], "citation_boundary": "Cite only curator-verified release rows and their source records; candidate gaps are curation leads.", "api_links": { "self": "/api/safety_triage?sequence=AUGCUACUGACUGA&target=PCSK9&modification=GalNAc&delivery=GalNAc&endpoint=hepatic&species=human", "dossier": 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