{ "version": "20260604_core_validation_v45", "scope_note": "Profiles are derived from current release/candidate text fields and modality labels; raw third-party text is not redistributed.", "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; 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" } ], "example_candidates": [ { "id": 16, "evidence_domain": "chemistry", "candidate_modality": "siRNA", "matched_terms": "galnac;lna;conjugate", "candidate_signal": "chemistry candidate; matched derived terms: galnac, lna, conjugate; source title: Pharmacokinetics and Pharmacodynamics of GalNAc-Conjugated siRNAs.", "confidence_label": "high_candidate", "validation_status": "candidate_needs_curator_review", "curator_decision": "pending", "source_title": "Pharmacokinetics and Pharmacodynamics of GalNAc-Conjugated siRNAs.", "pmid": "37589246" }, { "id": 17, "evidence_domain": "delivery", "candidate_modality": "siRNA", "matched_terms": "galnac;conjugated", "candidate_signal": "delivery candidate; matched derived terms: galnac, conjugated; source title: Pharmacokinetics and Pharmacodynamics of GalNAc-Conjugated siRNAs.", "confidence_label": "high_candidate", "validation_status": "candidate_needs_curator_review", "curator_decision": "pending", "source_title": "Pharmacokinetics and Pharmacodynamics of GalNAc-Conjugated siRNAs.", "pmid": "37589246" }, { "id": 20, "evidence_domain": "delivery", "candidate_modality": "siRNA", "matched_terms": "galnac;conjugated", "candidate_signal": "delivery candidate; matched derived terms: galnac, conjugated; source title: APOC3 siRNA and ASO therapy for dyslipidemia.", "confidence_label": "high_candidate", "validation_status": "candidate_needs_curator_review", "curator_decision": "pending", "source_title": "APOC3 siRNA and ASO therapy for dyslipidemia.", "pmid": "38334488" }, { "id": 24, "evidence_domain": "chemistry", "candidate_modality": "siRNA", "matched_terms": "galnac;lna;conjugate", "candidate_signal": "chemistry candidate; matched derived terms: galnac, lna, conjugate; source title: Mechanistic Insights into Hybridization-Based Off-Target Activity of GalNAc-siRNA Conjugates.", "confidence_label": "high_candidate", "validation_status": "curator_rejected", "curator_decision": "reject", "source_title": "Mechanistic Insights into Hybridization-Based Off-Target Activity of GalNAc-siRNA Conjugates.", "pmid": "40134378" }, { "id": 25, "evidence_domain": "delivery", "candidate_modality": "siRNA", "matched_terms": "galnac;conjugated", "candidate_signal": "delivery candidate; matched derived terms: galnac, conjugated; source title: Mechanistic Insights into Hybridization-Based Off-Target Activity of GalNAc-siRNA Conjugates.", "confidence_label": "high_candidate", "validation_status": "candidate_needs_curator_review", "curator_decision": "pending", "source_title": "Mechanistic Insights into Hybridization-Based Off-Target Activity of GalNAc-siRNA Conjugates.", "pmid": "40134378" }, { "id": 26, "evidence_domain": "offtarget", "candidate_modality": "siRNA", "matched_terms": "off-target;seed;silencing", "candidate_signal": "offtarget candidate; matched derived terms: off-target, seed, silencing; source title: Mechanistic Insights into Hybridization-Based Off-Target Activity of GalNAc-siRNA Conjugates.", "confidence_label": "high_candidate", "validation_status": "machine_precurated_v1", "curator_decision": "accept", "source_title": "Mechanistic Insights into Hybridization-Based Off-Target Activity of GalNAc-siRNA Conjugates.", "pmid": "40134378" }, { "id": 48, "evidence_domain": "chemistry", "candidate_modality": "ASO", "matched_terms": "galnac;lna;conjugate", "candidate_signal": "chemistry candidate; matched derived terms: galnac, lna, conjugate; source title: Pharmacokinetics and Safety of Pelacarsen, a GalNAc(3)-Conjugated Antisense Oligonucleotide Targeting Apo(a), in Participants With Mild Hepatic Impairment.", "confidence_label": "medium_candidate", "validation_status": "candidate_needs_curator_review", "curator_decision": "pending", "source_title": "Pharmacokinetics and Safety of Pelacarsen, a GalNAc(3)-Conjugated Antisense Oligonucleotide Targeting Apo(a), in Participants With Mild Hepatic Impairment.", "pmid": "41021771" }, { "id": 49, "evidence_domain": "delivery", "candidate_modality": "ASO", "matched_terms": "galnac;conjugated", "candidate_signal": "delivery candidate; matched derived terms: galnac, conjugated; source title: Pharmacokinetics and Safety of Pelacarsen, a GalNAc(3)-Conjugated Antisense Oligonucleotide Targeting Apo(a), in Participants With Mild Hepatic Impairment.", "confidence_label": "medium_candidate", "validation_status": "candidate_needs_curator_review", "curator_decision": "pending", "source_title": "Pharmacokinetics and Safety of Pelacarsen, a GalNAc(3)-Conjugated Antisense Oligonucleotide Targeting Apo(a), in Participants With Mild Hepatic Impairment.", "pmid": "41021771" } ] } ] }