{ "version": "20260604_core_validation_v45", "question": "Show GalNAc liver toxicity Grade A/B evidence", "answer_mode": "deterministic_grounded_read_only; llm_ready_payload_no_external_llm_call", "llm_status": "external_llm_disabled_by_default", "answer": "Found 16 curator-verified release records for this read-only query; showing 16. The answer is grounded only in OligoVigil release tables and linked source metadata.", "interpreted_query": { "domain": "toxicity", "grades": [ "A", "B" ], "modalities": [ "ASO", "siRNA", "ASO/siRNA mixed context" ], "target": "any", "term_groups": [ "galnac", "liver", "lna" ], "free_terms_seen": [ "GalNAc", "liver" ] }, "query_plan": { "allowed_tables": [ "toxicity_endpoint", "offtarget_evidence", "molecule", "source_document", "curation_audit" ], "candidate_table_policy": "excluded_from_answer; candidates require human promotion before release evidence", "write_access": false, "sql_template": "evidence_records(domain,target,limit=5000) + deterministic grade/modality/term filtering" }, "summary": { "records_considered": 626, "records_matched": 16, "records_shown": 16, "grade_counts": [ { "label": "B", "n": 12 }, { "label": "A", "n": 4 } ], "domain_counts": [ { "label": "toxicity", "n": 16 } ], "category_counts": [ { "label": "hepatic", "n": 13 }, { "label": "general safety", "n": 1 }, { "label": "hematologic", "n": 1 }, { "label": "renal; hepatic", "n": 1 } ], "source_count_shown": 10 }, "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", "ask_matched_terms": "galnac, liver, lna" }, { "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", "ask_matched_terms": "galnac, liver, lna" }, { "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", "ask_matched_terms": "galnac, liver, lna" }, { "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", "ask_matched_terms": "galnac, liver, lna" }, { "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", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 76, "canonical_name": "siRNA candidate from PMID 40503175", "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 > Therapeutic potential of GalNAc-siCIDEB in MASH; paragraph 16", "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": "Histological analysis revealed no treatment-related liver abnormalities, including fibrosis, necrosis, or hepatocellular degeneration (Figure 3G).", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "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; FIGURE 2 caption", "source_document_id": 1059, "source_title": "A Long-Term Human Liver Spheroid Model for Assessing Silencing and Durability of GalNAc-Conjugated siRNAs.", "pmid": "41949334", "source_pmcid": "PMC13059674", "doi": "10.1111/cts.70536", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41949334/", "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 signs of hepatotoxicity were observed under the conditions used.", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 177, "canonical_name": "Revusiran", "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": "Abstract; paragraph 1", "source_document_id": 1430, "source_title": "Nonclinical Safety Profile of Revusiran, a 1st-Generation GalNAc-siRNA Conjugate for Treatment of Hereditary Transthyretin-Mediated Amyloidosis.", "pmid": "31821125", "source_pmcid": "PMC6987735", "doi": "10.1089/nat.2019.0796", "source_url": "https://pubmed.ncbi.nlm.nih.gov/31821125/", "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 (NOAEL) in rats was 30 mg/kg based on reversible microscopic changes in liver", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 178, "canonical_name": "Stk25", "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": "B", "source_location": "Discussion; paragraph 23", "source_document_id": 2784, "source_title": "Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease.", "pmid": "30576769", "source_pmcid": "PMC6411916", "doi": "10.1016/j.jcmgh.2018.12.004", "source_url": "https://pubmed.ncbi.nlm.nih.gov/30576769/", "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": "remained within normal reference values in mice treated with GalNAc-Stk25 ASO", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 193, "canonical_name": "MKK4", "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": "Discussion; paragraph 52", "source_document_id": 1152, "source_title": "Dual targeted gene delivery strategy mediated by GalNAc-modified lipid nanoparticles enhances liver regeneration through specific knockdown of MKK4.", "pmid": "41970250", "source_pmcid": "PMC13067123", "doi": "10.1016/j.mtbio.2026.103059", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41970250/", "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": "both LNP-siMKK4 and GalNAc-LNP-siMKK4 induced less than 5% of hemolysis rate", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 238, "canonical_name": "revusiran", "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": "DISCUSSION; paragraph 57", "source_document_id": 2105, "source_title": "Safety evaluation of 2'-deoxy-2'-fluoro nucleotides in GalNAc-siRNA conjugates.", "pmid": "30820542", "source_pmcid": "PMC6468299", "doi": "10.1093/nar/gkz140", "source_url": "https://pubmed.ncbi.nlm.nih.gov/30820542/", "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": "Modest effects on cell viability and mitochondrial DNA were observed in vitro in a subset of cell types at high concentrations of 2′-F-nucleosides, typically not attained in vivo.", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 296, "canonical_name": "GalNAc3; GalNAc3-conjugated", "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": "B", "source_location": "PubMed abstract", "source_document_id": 1112, "source_title": "Safety and Tolerability of GalNAc(3)-Conjugated Antisense Drugs Compared to the Same-Sequence 2'-O-Methoxyethyl-Modified Antisense Drugs: Results from an Integrated Assessment of Phase 1 Clinical Trial Data.", "pmid": "38227794", "source_pmcid": null, "doi": "10.1089/nat.2023.0026", "source_url": "https://pubmed.ncbi.nlm.nih.gov/38227794/", "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": "However, there was a significant increase in mean alanine transaminase levels compared with placebo in the upper dose range of the unconjugated 2'MOE ASO group.", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 329, "canonical_name": "GalNAc3; GalNAc3-MOE; GalNAc3-conjugated", "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": "B", "source_location": "PubMed abstract", "source_document_id": 1465, "source_title": "Safety, Pharmacokinetic, and Pharmacodynamic Evaluation of a 2'-(2-Methoxyethyl)-D-ribose Antisense Oligonucleotide-Triantenarry N-Acetyl-galactosamine Conjugate that Targets the Human Transmembrane Protease Serine 6.", "pmid": "33431610", "source_pmcid": null, "doi": "10.1124/jpet.120.000222", "source_url": "https://pubmed.ncbi.nlm.nih.gov/33431610/", "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": "Suprapharmacologic doses of ISIS 702843 were well tolerated in NHPs after chronic dosing, and the data indicate that the overall safety profile is very similar to that of the unconjugated 2'-(2-methoxyethyl)-D-ribose (2'-MOE) ASOs.", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 717, "canonical_name": "revusiran (recovered B2 from PMID:28129130, 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": "B", "source_location": "Abstract; paragraph 1", "source_document_id": 2323, "source_title": "Clinical Proof of Concept for a Novel Hepatocyte-Targeting GalNAc-siRNA Conjugate.", "pmid": "28129130", "source_pmcid": "PMC5363199", "doi": "10.1016/j.ymthe.2016.10.019", "source_url": "https://pubmed.ncbi.nlm.nih.gov/28129130/", "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": "Revusiran was generally well tolerated, with transient, mild to moderate injection site reactions the most common treatment-emergent adverse events.", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 903, "canonical_name": "unspecified siRNA (v1 extraction artefact, pending source re-verification)", "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": "B", "source_location": "PubMed abstract", "source_document_id": 1166, "source_title": "SLN124, a GalNAc conjugated 19-mer siRNA targeting tmprss6, reduces plasma iron and increases hepcidin levels of healthy volunteers.", "pmid": "37497888", "source_pmcid": null, "doi": "10.1002/ajh.27015", "source_url": "https://pubmed.ncbi.nlm.nih.gov/37497888/", "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": "Accept B: PubMed abstract gives a direct abstract-level signal for hepatic/hepatotoxicity in siRNA; no full passage, so curator kept confidence limited.", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" }, { "evidence_domain": "toxicity", "entity_table": "toxicity_endpoint", "evidence_id": 1387, "canonical_name": "unspecified siRNA (v1 extraction artefact, pending source re-verification)", "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": "B", "source_location": "PubMed abstract", "source_document_id": 1478, "source_title": "Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial.", "pmid": "40179932", "source_pmcid": null, "doi": "10.1016/S0140-6736(25)00507-0", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40179932/", "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": "Accept B: PubMed abstract gives a direct abstract-level signal for hepatic/hepatotoxicity in siRNA; no full passage, so curator kept confidence limited.", "audited_at": "2026-06-07T02:20:35+00:00", "ask_matched_terms": "galnac, liver, lna" } ], "citations": [ { "pmid": "40919077", "doi": "10.1016/j.jhepr.2025.101516", "source_title": "Peginterferon-alpha-2a add-on to treatment with siRNA JNJ-73763989 in virologically suppressed chronic hepatitis B: The phase II PENGUIN study.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40919077/", "source_location": "Results > Safety; paragraph 22" }, { "pmid": "35736224", "doi": "10.1093/nar/gkac539", "source_title": "From bench to bedside: Improving the clinical safety of GalNAc-siRNA conjugates using seed-pairing destabilization.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/35736224/", "source_location": "RESULTS > GNA improves the therapeutic index in rats; paragraph 33" }, { "pmid": "34760338", "doi": "10.1016/j.omtn.2021.10.008", "source_title": "Drug discovery and development scheme for liver-targeting bridged nucleic acid antisense oligonucleotides.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/34760338/", "source_location": "Results > Evaluating the safety of the GalNAc conjugate in rat; paragraph 15" }, { "pmid": "29459660", "doi": "10.1038/s41467-018-02989-4", "source_title": "Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/29459660/", "source_location": "Results > Blocking siRNA-loaded RISC activity mitigates hepatotoxicity; paragraph 12" }, { "pmid": "40692538", "doi": "10.2147/IJN.S510937", "source_title": "Protective Effects of GalNac-Modified Red Blood Cell-Derived Extracellular Vesicles Against Liver Diseases.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40692538/", "source_location": "Results > Drugs-Loaded GalNac-RBC-EVs Were Non-Toxic to Mice; paragraph 42" }, { "pmid": "40503175", "doi": "10.1016/j.omtn.2025.102567", "source_title": "Targeting CIDEB alleviates liver steatosis and fibrosis in mouse MASH models.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/40503175/", "source_location": "Results > Therapeutic potential of GalNAc-siCIDEB in MASH; paragraph 16" }, { "pmid": "41949334", "doi": "10.1111/cts.70536", "source_title": "A Long-Term Human Liver Spheroid Model for Assessing Silencing and Durability of GalNAc-Conjugated siRNAs.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41949334/", "source_location": "Results > Treatment of Hepatic Spheroids With Chemically Modified GalNAc‐Conjugated siRNA; FIGURE 2 caption" }, { "pmid": "31821125", "doi": "10.1089/nat.2019.0796", "source_title": "Nonclinical Safety Profile of Revusiran, a 1st-Generation GalNAc-siRNA Conjugate for Treatment of Hereditary Transthyretin-Mediated Amyloidosis.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/31821125/", "source_location": "Abstract; paragraph 1" }, { "pmid": "30576769", "doi": "10.1016/j.jcmgh.2018.12.004", "source_title": "Targeted Delivery of Stk25 Antisense Oligonucleotides to Hepatocytes Protects Mice Against Nonalcoholic Fatty Liver Disease.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/30576769/", "source_location": "Discussion; paragraph 23" }, { "pmid": "41970250", "doi": "10.1016/j.mtbio.2026.103059", "source_title": "Dual targeted gene delivery strategy mediated by GalNAc-modified lipid nanoparticles enhances liver regeneration through specific knockdown of MKK4.", "source_url": "https://pubmed.ncbi.nlm.nih.gov/41970250/", "source_location": "Discussion; paragraph 52" } ], "follow_up_actions": { "open_evidence": "/api/evidence_records?domain=toxicity", "download_release": "/api/download/evidence_release.csv", "benchmark": "/api/benchmark", "citation": "/api/citation" }, "warnings": [ "This endpoint is a grounded query assistant, not a source of new curated evidence.", "Candidate records are intentionally excluded from answers until they pass the curation promotion gate.", "A future LLM layer should consume this JSON as grounding context and must cite returned sources." ] }