| assumption_id,assumption_category,assumption_text,impact,confidence,record_origin,source_basis,impact_on_generation,assumption_label,description,applies_to,risk_if_wrong,mitigation,assumption_type,source_id,assumption_name,source_ids,expected_use,evidence_source_id,rationale,generated_variables |
| ASM_001,synthetic_data_scope,Generated records are not measured experimental observations unless explicitly labeled as reported_in_paper.,Prevents overclaiming and preserves transparency.,high,method_assumption,,,,,,,,,,,,,,, |
| ASM_002,predictor_framework,"Sequence-derived, chemistry-derived, biophysical, and exposure variables jointly influence synthetic hepatotoxicity risk.",Defines the multivariable risk score and downstream readout generation.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_003,PS_content,Higher phosphorothioate content increases class-level synthetic hepatotoxicity risk in the generated data.,Affects chemical modification table and toxicity risk score.,medium,method_assumption,,,,,,,,,,,,,,, |
| ASM_004,offtarget_burden,Higher predicted off-target hybridization burden increases transcriptomic perturbation and stress response scores.,Affects biophysical_properties and toxicity_readouts.,medium,method_assumption,,,,,,,,,,,,,,, |
| ASM_005,GalNAc_delivery,"GalNAc conjugation is treated as liver-targeting context and modestly reduces extra-hepatic exposure-related synthetic risk, while preserving liver uptake relevance.",Affects synthetic risk score and source-role weighting.,medium,method_assumption,,,,,,,,,,,,,,, |
| ASM_006,human_models,"Human liver spheroid, primary human hepatocyte, HepaRG, and liver-on-chip records are marked as human-relevant model systems.",Affects assay metadata and translatability summaries.,high,method_assumption,,,,,,,,,,,,,,, |
| ASM_007,controls,"Positive and negative controls are generated as explicit benchmark rows with control_id, control_type, rationale, and provenance.",Makes the final dataset compliant with explicit control logic.,high,method_assumption,,,,,,,,,,,,,,, |
| ASM_008,nanoparticle_delivery,"Nanocarrier size, surface charge, PEGylation, ligand targeting, hepatic uptake, Kupffer clearance, immunogenicity, and oxidative stress are modeled as delivery-context variables that can modify synthetic hepatotoxicity readouts.",Adds delivery-system predictors and controls inspired by nanoparticle hepatology literature while preserving clear generated-value provenance.,medium,method_assumption,,,,,,,,,,,,,,, |
| ASM_009,hybrid_RNA_LNP_payload,"Hybrid siRNA+mRNA LNP payload architecture is modeled separately from direct hepatotoxicity, capturing PCSK9 knockdown, antigen-presentation enhancement, and immune-activation context as generated payload-system variables.","Adds RNA payload architecture, immune-activation, and antigen-presentation context without treating tumour-immunotherapy outcomes as direct oligo hepatotoxicity measurements.",medium,method_assumption,,,,,,,,,,,,,,, |
| ASM_010,APOB_ASO_lipid_homeostasis,"Mipomersen-like APOB ASO effects, MTTP activity context, and VLDL-apoB secretion are modeled as lipid-homeostasis variables separate from direct hepatotoxicity measurements.",Adds a lipid-export context table and controls that can help benchmark whether generated oligo records disturb lipid handling pathways.,medium_low,method_assumption,,,,,,,,,,,,,,, |
| ASM_011,MASLD_epigenetic_lipid_accumulation,"Super-enhancer/H3K27ac activity, CEBPB-SULT1B1 signaling, oleate-induced lipid accumulation, and JQ1- or siRNA-like rescue effects are modeled as hepatocyte liver-disease context variables separate from direct measured oligo toxicity.",Adds epigenetic/lipid-accumulation context and controls that make the generated dataset more useful for distinguishing oligo toxicity from underlying MASLD-like liver stress.,medium,method_assumption,,,,,,,,,,,,,,, |
| ASM_012,ANGPTL3_liver_safety_platform_context,ANGPTL3 ASO-vs-siRNA liver-safety variables are generated as platform/target-inhibition context |
| ASM_013,PNPLA3_precision_genetics_context,"PNPLA3 I148M genotype, adiposity/metabolic stress, insulin resistance, sex-related susceptibility, and genotype-targeted siRNA/ASO response are modeled as liver-disease context variables separate from direct measured oligonucleotide hepatotoxicity.","Adds source-informed PNPLA3 precision-medicine controls and predictors for hepatic-fat liability, lipid-droplet biology, and therapeutic knockdown response.",medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_014,extrahepatic_cholesterol_siRNA_delivery_context,"Cholesterol-conjugated, chemically modified siRNA records are modeled as extrahepatic delivery contexts with skeletal-muscle/diaphragm knockdown, possible liver exposure, and low liver-marker signal unless combined with independent hepatotoxicity risk factors.","Adds source-informed extrahepatic delivery and tolerability variables, helping distinguish tissue-distribution context from direct oligo hepatotoxicity.",medium,method_assumption,,,,,,,,,,,,,,, |
| ASM_015,patient_customized_ASO_design_safety_workflow_context,"Patient-customized splice-modulating ASO records are modeled as design, validation, dosing, PK, toxicology, and monitoring workflow context; they do not imply direct hepatotoxicity unless combined with separate liver-risk variables.","Adds source-informed ASO workflow variables useful for documenting sequence-specific design, off-target screening, preclinical toxicology, and clinical monitoring in oligo development.",medium,method_assumption,,,,,,,,,,,,,,, |
| ASM_016,ASO_metabolic_NAFLD_safety_challenges_context,"ASO metabolic/NAFLD records model hepatocyte targeting, RNase-H1 gapmer mechanisms, DNL/lipid-partitioning target benefit, ALT/AST/GGT hepatic-injury monitoring, sequence-motif toxicity, type-I-interferon response, and kidney-injury monitoring as generated context variables rather than measured outcomes.",Adds source-informed ASO metabolic-liver disease and safety-challenge variables that help distinguish therapeutic steatosis improvement from oligo-related hepatic or off-target toxicity.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_017,sequence_modification_hepatotoxicity_prediction,"For LNA/phosphorothioate gapmer-style records, sequence composition and modification pattern are modeled as contributors to hepatotoxic potential using generated dinucleotide-feature, ALT-threshold, prediction-confidence, and redesign-risk-reduction variables.","Adds source-informed sequence/modification toxicity predictors and controls, improving explicit modeling of oligo-intrinsic hepatotoxic potential beyond generic PS, dose, and off-target burden variables.",high_for_context_medium_for_generated_values,method_assumption,,,,,,,,,,,,,,, |
| ASM_018,HSD17B13_rapirosiran_clinical_PK_PD_safety_context,"Generated rapirosiran/HSD17B13 rows encode phase-I clinical context as synthetic/inferred proxies: GalNAc-siRNA ASGPR liver uptake, short plasma PK, prolonged liver PD, dose-dependent HSD17B13 mRNA reduction, ALT/AST/NAS context, and no drug-induced liver injury flag. These are not copied patient-level measurements.","Improves clinical relevance of low-hepatotoxicity GalNAc-siRNA controls, target-knockdown variables, disease-background comparator variables, and provenance-labeled clinical safety fields.",,method_assumption,RAPIROSIRAN_SANYAL_2025,,,,,,,,,,,,,, |
| ASM_019,VIR2218_ESCplus_seed_region_safety_context,"VIR-2218/ALN-HBV source evidence is represented as generated context linking seed-region chemistry, off-target mitigation, ALT safety signals, and antiviral PD; row-level generated values are proxies and not patient-level clinical data.",Adds a direct sequence-modification safety module that helps distinguish parent siRNA seed-mediated off-target ALT risk from ESC+ seed-stabilized lower-ALT context.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_020,zilebesiran_AGT_GalNAc_siRNA_RAAS_safety_context,"Zilebesiran-like AGT-targeted GalNAc-siRNA records are modeled as supporting hepatocyte-targeting, endosomal-depot, RISC-recycling, prolonged-PD, blood-pressure, hyperkalemia, hypotension, and renal-function monitoring context. They are not treated as direct oligonucleotide-induced hepatotoxicity evidence.",,,method_assumption,DUDZICZ_ZILEBESIRAN_HTN_REVIEW_2025,Adds AGT/RAAS clinical-platform variables and safety-monitoring controls while keeping hepatotoxicity scoring mostly low/moderate unless other oligo-risk features dominate.,,,,,,,,,,,,, |
| ASM_021,siRNA_bulge_offtarget_design_context,"Short siRNA guide-strand bulges are modeled as design and off-target-prediction features. Tolerated guide-passenger bulges are activity-context variables, while terminal guide-target bulges/nucleotide omissions are off-target risk variables rather than direct hepatotoxicity measurements.",,,method_assumption,HAUPTMANN_SIRNA_BULGES_GALNAC_2022,"Adds bulge length, position, region, guide-passenger versus guide-target mode, GalNAc uptake compatibility, target repression, and off-target-degenerate-target predictors while keeping direct hepatotoxicity effects modest.",,,,,,,,,,,,, |
| ASM_022,FBLL1_HCC_malignant_hepatocyte_context,"FBLL1/HCC multi-omics and spatial transcriptomics evidence is modeled as liver-disease and oncogenic-state context. It can inform HCC-related background, hepatocyte dedifferentiation, c-Myc/EGFR-MAPK signaling, and siRNA knockdown-response fields, but it is not treated as direct evidence of therapeutic oligonucleotide-induced hepatotoxicity.",,,method_assumption,XIE_FBLL1_HCC_SPATIAL_MULTIOMICS_2026,"Adds FBLL1 expression, malignant-hepatocyte enrichment, spatial tumor-niche, siRNA-knockdown, overexpression tumorigenesis, ALB/MYC/EGFR-ligand, and EGFR-MAPK context variables while keeping direct hepatotoxicity modifiers small.",,,,,,,,,,,,, |
| ASM_023,GalNAc_LNP_siMKK4_liver_regeneration_context,"GalNAc-LNP-siMKK4 evidence is modeled as a hepatocyte-targeted siRNA delivery, biocompatibility, and liver-regeneration context. It improves variables related to LNP formulation, ASGPR hepatocyte targeting, MKK4-selective knockdown, p38/JNK pathway balance, hepatocyte proliferation, apoptosis reduction, and liver-function recovery, but it is not treated as direct evidence of oligonucleotide-induced hepatotoxicity.",,,method_assumption,ZHAI_GALNAC_LNP_SIMKK4_LIVER_REGEN_2026,"Adds source-informed dual-targeting LNP parameters, delivery-quality controls, ACLF liver-injury model context, and regeneration/rescue variables while keeping direct hepatotoxicity modifiers mostly low unless the background injury model is explicitly represented.",,,,,,,,,,,,, |
| ASM_024,,,,,method_assumption,,,OGT_sEV_LSEC_capillarization_MASLD_context,"Lipotoxic hepatocyte-derived sEVs can be represented as a supporting MASLD liver-microenvironment module in which sEV cargo OGT increases HNF1a O-GlcNAcylation, Ang-2 expression, LSEC capillarization/defenestration, and ALT/AST-associated disease stress; OGT knockdown or BAGN-like O-GlcNAc inhibition reduces this context.",ogt_sev_lsec_masld_context.csv,Could overstate relevance of extracellular-vesicle biology to oligonucleotide hepatotoxicity if treated as direct oligo toxicity rather than liver-context evidence.,"Label as supporting context only, keep value_origin/provenance fields, and do not treat EV or BAGN effects as measured therapeutic oligo toxicity.",,,,,,,, |
| ASM_025,,,,medium_high_for_context_low_for_direct_oligotox,method_assumption,,,,"HBx-induced MALAT1, m6A modification, IGF2BP3-mediated nuclear-cytoplasmic shuttling/stabilization, and ASO-MALAT1 suppression of HBV-related HCC are encoded as liver-disease and ASO-intervention context variables. These variables support mechanistic diversity and controls but are not treated as direct oligonucleotide hepatotoxicity evidence.",,,,supporting_HBV_HCC_ASO_MALAT1_context,DU_MALAT1_HBV_HCC_ASO_2025,,,,,, |
| ASM_026,,,,medium_high_for_context_low_for_direct_oligotox,method_assumption,,,,"CD133-positive cancer stem cell enrichment, MYH9/Wnt/beta-catenin signaling, multikinase inhibitor resistance, and VNP-siCD133 combination therapy are encoded as MASLD-HCC liver-disease and siRNA-intervention context variables. These variables support source-grounded therapeutic-context diversity but are not treated as direct oligonucleotide hepatotoxicity evidence.",,,,supporting_MASLD_HCC_CD133_siRNA_combination_therapy_context,PAN_CD133_MASLD_HCC_SIRNA_2025,,,,,, |
| ASM_027,,,,high_for_delivery_and_context_medium_for_generalized_oligotox,method_assumption,,,,"GalNAc-modified RBC-derived EVs are encoded as a hepatocyte-targeted biomimetic delivery context for ASO, siRNA, and small-molecule co-delivery, capturing ASGPR uptake, stability, ALF miR-155-ASO rescue, NAFLD PJ34/PARP-1 rescue, HCC Rab7-siRNA/PJ34 retention, ALT/AST and histopathology safety, and PANoptosis/steatosis/tumor variables.",,,,supporting_GalNAc_RBC_EV_hepatocyte_delivery_ASO_siRNA_liver_disease_context,HUANG_GALNAC_RBC_EV_LIVER_DISEASE_2025,,,,,, |
| ASM_028,,,,high_for_clinical_liver_risk_context_low_for_direct_oligotox,method_assumption,,,,"MELD-Plus is encoded as a clinical liver-severity and post-discharge mortality-risk context module using structured EMR variables: bilirubin, creatinine, albumin, INR, WBC, length of stay, age, sodium, and total cholesterol. This module helps connect generated hepatotoxicity and liver-injury profiles to clinical cirrhosis severity and outcome risk, but it is not treated as direct oligonucleotide hepatotoxicity evidence.",,,,supporting_clinical_liver_severity_MELD_Plus_context,KARTOUN_MELD_PLUS_CIRRHOSIS_2017,,,,,, |
| ASM_029,,,,,method_assumption,,,,"Alcohol-related liver disease modules can provide contextual liver-stress axes for generated OligoTox records: acetaldehyde/aldehyde burden, ROS, lipid peroxidation, mitochondrial injury, antioxidant reserve, and ALDH2/Nrf2 loss-of-rescue logic.",,,,,,ALD_ALDH2_Nrf2_oxidative_stress_context,MA_FORMONONETIN_ALDH2_ALD_2025,supporting_liver_context_not_direct_oligo_hepatotoxicity,,, |
| ASM_030,,,,,method_assumption,,,,"Non-hepatic in vivo siRNA nanoparticle studies can provide useful delivery-system safety context when they include systemic tolerability, hemolysis, ALT/AST, histopathology, particle stability, and RNAi knockdown fields; they should not be treated as direct oligo-induced hepatotoxicity evidence.",,,,,,calcium_phosphate_hybrid_nanoparticle_siRNA_systemic_safety_context,VALLE_HOXB7_HNP_TAMOXIFEN_BREAST_2024,supporting_delivery_platform_safety_context,,, |
| ASM_031,,,,,method_assumption,,,,"Engineered small-extracellular-vesicle RNA loading papers can provide delivery-platform fields for OligoTox when they include small-RNA cargo class, loading method, sEV biogenesis mechanism, hepatocyte delivery, target knockdown, lipid/metabolic readouts, ALT/AST, organ histology, and explicit systemic safety observations. These are delivery/safety context fields, not direct evidence of oligonucleotide-induced hepatotoxicity unless liver injury is measured as an outcome.",,,,,,PMEVL_sEV_small_RNA_loading_hepatic_siRNA_delivery_context,WANG_PMEVL_SEV_SMALL_RNA_PCSK9_2026,supporting_sEV_RNA_delivery_and_hepatic_safety_context,,, |
| ASM_032,,,,,method_assumption,,,,"Therapeutic oligonucleotide safety records should distinguish on-target exaggerated pharmacology, hybridization-dependent off-target activity, sequence-dependent hybridization-independent liver/kidney/inflammatory toxicity, Cmax-driven complement/coagulation effects, delivery-platform effects, long tissue half-life, restricted productive uptake, species cross-reactivity, surrogate molecules, and monitoring endpoints. These fields organize generated safety context; they do not convert generated records into measured toxicology observations.",,,,,,therapeutic_oligonucleotide_preclinical_safety_framework,ANDERSSON_PRECLINICAL_OLIGO_SAFETY_2022,direct_preclinical_safety_assessment_schema_and_controls,,, |
| ASM_033,IFN_alpha_HCC_disulfidptosis_context,"IFN-alpha-induced disulfidptosis-like phenotypes in HepG2/Huh7 cells are encoded as supporting liver-cell stress context, not as direct therapeutic-oligonucleotide hepatotoxicity evidence.","Adds variables for disulfide-bond accumulation, NADPH depletion, F-actin collapse, D-penicillamine rescue, SLC7A11 knockdown aggravation, and B2M/USP18/PSME1 candidate-gene upregulation.",,method_assumption,,,,,,,,,,,,,BI_IFNA_DISULFIDPTOSIS_HCC_2026,, |
| ASM_034,GalNAc_siRNA_nonclinical_safety_platform,ESC GalNAc-siRNA nonclinical safety is encoded as a platform-level safety framework distinguishing seed-mediated off-target hepatotoxicity from mostly nonadverse liver/kidney/RES distribution and accumulation findings.,"Adds ASGPR uptake, ESC chemistry, rat/monkey sensitivity, exaggerated-dose multiples, liver/kidney/RES histology, reversibility, genotoxicity/safety-pharmacology status, and seed-region off-target hepatotoxicity screening variables.",,method_assumption,,,,,,,,,,,,,JANAS_GALNAC_RNAI_NONCLINICAL_SAFETY_2018,, |
| ASM_035,Inclisiran_PCSK9_real_world_clinical_context,"Inclisiran real-world familial-hypercholesterolemia data are encoded as supporting clinical PCSK9 GalNAc-siRNA efficacy/tolerability context, not as a direct hepatotoxicity mechanism.","Adds six-month LDL-C/ApoB/non-HDL-C/Lp(a) and PWV response variables, LDL-C target-attainment context, and stable ALT/AST/CPK monitoring proxies.",,method_assumption,,,,,,,,,,,,,BOSCO_INCLISIRAN_FH_REALWORLD_2025,, |
| ASM_036,GalNAc_ASGPR_liver_delivery_clinical_translation,"GalNAc-mediated ASGPR uptake is encoded as a core liver-delivery mechanism that changes hepatocyte exposure, potency, dosing requirements, and safety interpretation for ASO and siRNA therapeutics.","Adds ASGPR receptor-capacity, GalNAc valency/cluster, ASO hepatocyte uptake shift, siRNA ESC/ESC+ chemistry, endosomal escape, Reversir reversal context, clinical pipeline context, and safety-monitoring variables.",,method_assumption,,,,,,,,,,,,,DEBACKER_GALNAC_LIVER_DELIVERY_REVIEW_2020,, |
| ASM_037,siRNA_pharmacology_and_clinical_development_context,"General siRNA mechanism, pharmacology, delivery, immune/off-target, chemical-modification, and clinical-development concepts are encoded as framework variables for interpreting OligoTox records rather than as direct hepatotoxicity measurements.","Adds RISC/AGO2 mechanism fields, guide/seed/central-region context, naked-siRNA PK barriers, GalNAc/LNP delivery context, immune/off-target screening variables, and approved/developing siRNA clinical-translation flags.",,method_assumption,,,,,,,,,,,,,RANASINGHE_SIRNA_PHARMACOLOGY_REVIEW_2023,, |
| ASM_038,,,,,method_assumption,,"Adds explicit positive/negative ASO controls, experimental-design endpoints, off-target selectivity variables, and screening feasibility logic aligned with Phase 2 experimental-design and translatability scoring.",,"LNA gapmer ASO hepatotoxicity risk can be represented as a function of oligo length/design, predicted hybridization-mediated off-target burden, confirmed transcriptome-wide selectivity, plasma ALT/AST response, liver-weight response, and acute/repeat-dose screen concordance.",,,,,,,,,KAMOLA_ASO_HEPATOTOX_SCREEN_2017,The source paper reports that a 3-day acute mouse screen using ALT/AST and liver weight gave a similar hepatotoxicity ranking to a longer repeat-dose study and that more hepatotoxic ASOs were less selective with more potent OTEs., |
| ASM_039,,,,,method_assumption,,"Adds a supporting preclinical LNP-ASO module with no-hepatotoxicity control, liver/vascular readouts, endothelial inflammation variables, and translatability-relevant safety monitoring. Because the source is a preprint, confidence is capped below peer-reviewed modules.",,"LNP-delivered LNA-gapmer ASO safety and translatability context can include endothelial-targeted knockdown, ALT/AST liver-function monitoring, lipid-profile endpoints, liver steatosis/fibrosis markers, inflammatory gene signatures, and endothelial-hepatocyte paracrine effects.",,,,,,,,,LIU_ENDOTHELIAL_AGO1_LNP_ASO_2025,"The source preprint reports LNP-delivered AGO1-ASO in an atherogenic mouse model, with improved lipid and liver-function context and no evident ALT/AST hepatotoxicity signal, while mechanistic studies connect endothelial AGO1 to NF-kB-driven inflammation.", |
| ASM_040,,,,,method_assumption,,"Adds supporting preclinical ASO context for negative safety controls, extrahepatic ASO exposure, GYS1/GYS2 specificity, treatment timing, ERT combination, and systemic clinical-chemistry monitoring. Confidence is capped because the source is a preprint and is not direct OligoTox hepatotoxicity evidence.",,"Systemic ASO tolerability modules should include extrahepatic target contexts, isoform-specificity concerns, organ-weight monitoring, ALT/AST, BUN, CK, treatment timing, and combination-therapy variables even when the primary therapeutic tissue is not liver.",,,,,,,,,WEISS_GYS1_ASO_POMPE_PREPRINT_2024,"The GYS1 Pompe preprint reports a systemic PS-cEt RNase-H1 gapmer ASO dosed subcutaneously in mice, alone and with enzyme replacement therapy, with muscle/heart pharmacology and explicit tolerability monitoring including liver transaminases, BUN, CK, and organ weights.", |
| ASM_041,,,,,method_assumption,,,,"Cholestatic hepatobiliary injury context can be represented using DDC/recovery-state variables, ALT/ALP/bilirubin/cholesterol, cholangiocyte activation, CX3CL1-CX3CR1 macrophage recruitment, PICSS inflammatory signaling, NF-YA/TGFβ1 fibrogenic signaling, and recovery-resolution indicators.",,,,,,,,,OLSON_CHOLANGIOCYTE_CHOLESTASIS_2025,Olson et al. 2025 provides a reversible murine cholestasis time course and mechanistic cholangiocyte transcriptomic/siRNA validation context relevant to liver-injury endpoint diversity and translatability., |
| ASM_042,,,,,method_assumption,,"Adds direct peer-reviewed preclinical oligo hepatotoxicity evidence to the Phase 2 package, improving coverage of explicit controls, source-provenanced liver readouts, dose/sequence dependence, reversibility, and assay documentation.",,"AmNA-modified phosphorothioate PCDHA11 ASO records model dose-dependent, sequence-dependent, reversible liver-enzyme signals using AST, ALT, ALP, bilirubin, renal-marker, body-weight, histology, target-specificity, and off-target-screening variables.",,,,,,,,,KANDA_PCDHA11_AMNA_ASO_2024,"Kanda et al. 2024 reports screening of 54 AmNA-modified anti-PCDHA11 ASOs, selected ASOs with in vitro/in vivo activity, weekly intraperitoneal mouse toxicity testing at multiple doses, dose/sequence-dependent AST/ALT/ALP elevation, recovery after treatment cessation, and combined bioinformatics/microarray off-target assessment.", |
| ASM_043,PS_ASO_DNA_damage_response_toxicity_mechanism,"Phosphorothioate ASOs can trigger concentration-dependent nuclear condensate/PS-body formation, repair-enzyme binding, and DNA-damage-response activation independent of direct DNA breaks; generated values model this as a chemistry-driven toxicity mechanism rather than a sequence-specific target effect.","Adds a mechanistic ASO toxicity table with PS-vs-PO contrast, DNA-PKcs/ATM/PARP1/ATR activity proxies, checkpoint activation, homologous-recombination suppression, and toxic DNA-lesion risk.",medium_high,method_assumption,,,,,,,,,,,,,HJELMGREN_PS_ASO_DDR_2026,, |
| ASM_044,ROS_responsive_GalNAc_siRNA_MASH_delivery_context,ROS-responsive shell disassembly combined with GalNAc/ASGPR hepatocyte targeting can be modeled as a disease-state-selective siRNA delivery context that may reduce steatosis and improve ALT/AST/albumin proxies while still requiring nanocarrier safety monitoring.,"Adds a targeted siRubicon MASH delivery table capturing ROS trigger, ASGPR uptake, hepatocyte specificity, lipophagy activation, steatosis reduction, off-target organ retention, and liver-function readouts.",medium_high,method_assumption,,,,,,,,,,,,,LAN_SIRUBICON_ROS_GALNAC_MASH_2025,, |
| ASM_045,scpBNA_scpBNA2_ASO_chemistry_safety,Cycloalkane-bridged BNA modifications are modeled as chemistry-level safety modifiers that can reduce hepatotoxicity proxies while preserving activity.,Adds v1.0 generated source-specific module variables and validation checks.,medium_high,method_assumption,,,,,,,,,,,,,YAMAGUCHI_SCPBNA2_REDUCED_HEPATOTOX_2025,, |
| ASM_046,siCyp2e1_LNP_APAP_liver_injury_intervention,"Cyp2e1-targeted siRNA LNP treatment is modeled as a liver-injury intervention context for APAP-driven toxic-metabolite formation, oxidative stress, inflammation, necrosis, and ALT/AST.",Adds v1.0 generated source-specific module variables and validation checks.,medium_high,method_assumption,,,,,,,,,,,,,LIU_CYP2E1_LNP_APAP_AILI_2025,, |
| ASM_047,NANP_liver_cell_type_targeting_and_offtarget_distribution,"Lipid-functionalized nucleic acid nanoparticles are modeled with cell-type targeting variables because ligand chemistry, valency, biomolecular corona, LDLR/SR-B1 engagement, and macrophage/LSEC association jointly shape delivery context.",Adds v1.0 generated source-specific module variables and validation checks.,medium_high,method_assumption,,,,,,,,,,,,,KIM_NANP_LIPID_LIVER_TARGETING_2026,, |
| ASM_048,RNA_nanoparticle_liver_cancer_multitarget_platform,"Self-assembling RNA nanoparticles are modeled as a liver-cell RNAi platform with multitarget knockdown, tumor-growth/activity endpoints, and explicit off-target/cytotoxicity dose-window variables.",Adds v1.0 source-specific module variables and explicit Phase 2 judging-criteria evidence outputs.,medium_high,method_assumption,,,,,,,,,,,,,SUN_HCC_RNA_NANOPARTICLE_MULTITARGET_2026,, |
| ASM_049,asymmetric_siRNA_DCA_delivery_safety_design,"Asymmetric siRNA design, VP modification, reduced seed/passenger off-target risk, 2prime-OMe/2prime-F/PS tradeoffs, and DCA conjugation are modeled as delivery and safety-design variables.",Adds v1.0 source-specific module variables and explicit Phase 2 judging-criteria evidence outputs.,medium_high,method_assumption,,,,,,,,,,,,,MEKONNEN_MYC_ASIRNA_DCA_TNBC_2025,, |
| ASM_050,multifunctional_HDO_delivery_design_context,Multifunctional HDOs are modeled as non-liver delivery-design context: ligand/peptide functionalization can improve intracellular delivery and gene silencing while requiring careful off-target/toxicity tracking.,Adds v1.0 source-specific module variables and explicit Phase 2 judging-criteria evidence outputs.,medium_high,method_assumption,,,,,,,,,,,,,SOUSA_HDO_MULTIFUNCTIONAL_HELA_2022,, |
| ASM_051,judging_criteria_are_output_tables,"Challenge judging criteria are represented directly in generated alignment, gap, readiness, validation, and reproducibility output tables.",Adds v1.0 source-specific module variables and explicit Phase 2 judging-criteria evidence outputs.,medium_high,method_assumption,,,,,,,,,,,,,MEMO_OLIGOTOX_PHASE2_ALIGNMENT,, |
| ASM_052,AGT_GalNAc_siRNA_development_toxicology,"Systematic siRNA development is modeled as a linked design-to-toxicology process: sequence screening, modification patterns, GalNAc delivery, off-target prediction limits, RNAseq off-target evidence, ALT/AST/urea/histopathology safety, and duration of AGT knockdown.",Adds direct siRNA toxicology and model-gap variables highly aligned with Phase 2 scoring.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_053,CpG_ODN_macrophage_APAP_immunomodulation,"CpG ODN is modeled as an immunomodulatory oligodeoxynucleotide context in APAP liver injury where macrophage TLR9/NF-kB activation can upregulate IRG1/ACOD1, increase itaconate, reduce ROS/apoptosis, and modify liver injury readouts.",Adds immune-cell and nonparenchymal-cell context for oligo-related liver injury interpretation.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_054,oligonucleotide_aptamer_PET_PK_biodistribution,"PET-labeled aptamers are modeled as a translational ADME/PK layer with organ exposure, renal/biliary excretion, liver/kidney/spleen burden, and target-tumor visualization context.","Adds tissue PK and biodistribution evidence for feasibility, rigor, and translational utility.",medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_055,deferred_context_sources,"HCC chromatin/DGAT1 and autoimmune-hepatitis ceRNA sources are tracked in triage and gap maps but not promoted into full modules because they add target-biology/liver-context evidence rather than direct oligo toxicity, delivery, or toxicology data.",Protects dataset rigor by avoiding over-integration of weakly aligned sources.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_056,ASO_PNA_BROTHERS_toxicity_mitigation,BROTHERS ASO/PNA duplexes are modeled as a direct ASO-safety mechanism that reduces hybridization-independent protein binding and hybridization-dependent RNA off-targets while preserving on-target activity when thermodynamic/toehold parameters are appropriate.,Adds direct mechanistic predictors for off-target toxicity mitigation and therapeutic-margin modeling.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_057,APOC3_GalNAc_siRNA_SAR_duration_safety,"Long-acting APOC3 GalNAc-siRNA design is modeled as a chemistry-SAR/duration/tolerability problem: scaffold, 2-F burden, PS/VP/MOE/OMe pattern, AGO2/RISC context, potency, durability, and rodent/NHP tolerability.",Adds high-value translational siRNA design and long-duration safety context.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_058,GalNAc_siRNA_LCMS_bioanalysis_reproducibility,"GalNAc-siRNA plasma bioanalysis is modeled as a measurement-quality layer with DPPT recovery, LLOQ, matrix interference, parent/metabolite distinction, and PK suitability.","Strengthens feasibility, rigor, transparency, and reproducibility evidence.",medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_059,oral_modified_NA_liver_fibrosis_context,"Orally administered nuclease-resistant miR-29a-like RNA-DNA hybrids are modeled as supporting liver-delivery/fibrosis context with LNA, PS, 2-F, COL1A1/PDGFC suppression, and CCl4 fibrosis readouts.",Adds modified nucleic-acid liver-delivery and fibrosis biology without overclaiming intrinsic OligoTox toxicity evidence.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_060,deferred_multi_siRNA_context,"The branched GP73/hTERT multi-siRNA HCC paper is tracked but deferred because it overlaps existing Hep3B/RNA nanoparticle modules and is less directly relevant to systemic oligo toxicity than the selected BROTHERS, APOC3, LC/MS, and fibrosis modules.",Protects package focus and reviewer trust by avoiding noisy duplication.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_080,GalNAc_siRNA_MASH_CIDEB_specificity,"GalNAc-siCIDEB is modeled as a liver-targeted siRNA module where hepatocyte ASGPR uptake, chemical stabilization, isoGNA seed/specificity design, target knockdown, steatosis/fibrosis reversal, and no-observed-toxicity context jointly define a direct MASH safety-efficacy scenario.","Adds v1.0 source-specific variables aligned to OligoTox Phase 2 ability-to-solve, impact, rigor, and reproducibility criteria.",medium_high,method_assumption,,,,,,,,,,,,,LIN_GALNAC_SICIDEB_MASH_STEATOSIS_FIBROSIS_2025,, |
| ASM_081,ASO_late_onset_toxicity_chemistry_mitigation,"Late-onset ASO neurotoxicity is modeled as a cross-organ oligo safety dimension influenced by gapmer chemistry, PS/protein binding, p53/paraspeckle stress, and site-specific 5prime-cyclopropylene or 2prime-OMe modifications that can change toxicity without eliminating knockdown.","Adds v1.0 source-specific variables aligned to OligoTox Phase 2 ability-to-solve, impact, rigor, and reproducibility criteria.",medium_high,method_assumption,,,,,,,,,,,,,KURODA_ASO_LATE_ONSET_NEUROTOX_5CP_MODIFICATIONS_2025,, |
| ASM_082,GalNAc_siRNA_MASLD_CEBPB_liver_homeostasis,"GalNAc-siCEBPB is modeled as a direct liver-targeted siRNA module linking target knockdown to steatosis reduction, albumin/bilirubin/lipid/glucose metabolic improvements, and unchanged ALT/AST safety context under continued diet stress.","Adds v1.0 source-specific variables aligned to OligoTox Phase 2 ability-to-solve, impact, rigor, and reproducibility criteria.",medium_high,method_assumption,,,,,,,,,,,,,KHORSANDI_GALNAC_SICEBPB_MASLD_HOMEOSTASIS_2026,, |
| ASM_083,trivalent_disulfide_oligo_delivery,"Trivalent disulfide-unit masked ODNs are modeled as a supporting delivery-chemistry platform with thiol-exchange-mediated uptake, low cytotoxicity, and liver distribution variables, distinct from LNP/GalNAc delivery.","Adds v1.0 source-specific variables aligned to OligoTox Phase 2 ability-to-solve, impact, rigor, and reproducibility criteria.",medium_high,method_assumption,,,,,,,,,,,,,WANG_TRIVALENT_DISULFIDE_MASKED_ODN_DELIVERY_2024,, |
| ASM_108,,Human HSC LARP6 knockdown and 3D MASH/MetALD liver spheroid evidence are encoded as fibrosis-relevant RNAi perturbation context rather than direct hepatocyte toxicity.,,,method_assumption,,,,,,,,,KIM_LARP6_HSC_FIBROSIS_DSI_RNA_2026,LARP6_HSC_fibrosis_dsiRNA_module,,,,,"HSC activation, collagen translation/expression, JUNB regulation, dsiRNA knockdown, and human spheroid fibrosis-attenuation variables." |
| ASM_109,,RNAi/REVERSIR AAV transgene regulation is encoded as a safety-engineering and controllability context for liver-directed nucleic-acid interventions.,,,method_assumption,,,,,,,,,SUBRAMANIAN_RNAI_RHEOSTAT_AAV_TRANSGENE_2023,RNAi_rheostat_AAV_transgene_control_module,,,,,"Reversible silencing, induction, shRNA/siRNA control, GalNAc delivery, off-target minimization, and clinical-translatability variables." |
| ASM_110,,Rat hepatotoxicity from some GalNAc-siRNAs is modeled as primarily RISC-loaded guide-strand seed-mediated off-target repression rather than class-wide chemistry toxicity.,,,method_assumption,,,,,,,,,JANAS_GALNAC_SIRNA_OFFTARGET_RAT_HEPATOTOX_2018,GalNAc_siRNA_seed_offtarget_hepatotoxicity_module,,,,,"RISC loading, 5-prime capping rescue, seed-region changes, GNA destabilization, transcriptome seed-match enrichment, ALT/AST, bilirubin, necrosis, degeneration, and mitigation variables." |
| ASM_111,,"DILImap/ToxPredictor is encoded as a modeling-rigor reference for human hepatocyte transcriptomic DILI prediction, not as oligo-specific toxicity evidence.",,,method_assumption,,,,,,,,,BERGEN_DILIMAP_TOXPREDICTOR_DILI_2025,human_hepatocyte_DILI_toxicogenomics_modeling_module,,,,,"PHH RNA-seq, dose-resolved safety margins, blind validation, sensitivity/specificity, mitochondrial/oxidative/immune/metabolic signatures, and ML validation variables." |
| ASM_124,GalNAc_siRNA_RISC_seed_offtarget_hepatotoxicity,GalNAc-siRNA off-target hepatotoxicity records model miRNA-like antisense seed-mediated RISC activity as separable from intended AGO2-mediated target cleavage |
| ASM_125,approved_oligonucleotide_chemistry_delivery_landscape,"Approved oligonucleotide chemistry records are used to standardize modification and delivery categories such as phosphorothioate, 2prime-F, 2prime-OMe, 2prime-MOE, PMO, LNP, and GalNAc; they are not treated as measured toxicity outcomes.",Improves data dictionary consistency and chemistry/platform interpretability.,high,method_assumption,,,,,,,,,,,,,,, |
| ASM_126,PNPLA3_AZD2693_precision_MASH_ASO,"AZD2693 records model PNPLA3 148M homozygous precision-therapy context, target engagement, liver fat response, inflammation biomarkers, and favorable phase 1 tolerability as generated evidence variables.",Adds original PNPLA3 ASO clinical target-engagement context beyond review-level PNPLA3 background.,high,method_assumption,,,,,,,,,,,,,,, |
| ASM_127,HSD17B13_human_genetics_and_ASO_translation,HSD17B13 records combine human genetic protection rationale with ASO preclinical knockdown evidence |
| ASM_128,preclinical_model_selection_for_NATs,"Preclinical model-selection variables encode whether the target sequence is species-aligned, surrogate, humanized, or human-cell-only; sequence mismatch can change measured ASO/siRNA activity and therefore is treated as a model-validity modifier.",Adds model-system rigor to interpretation of synthetic assay records.,high,method_assumption,,,,,,,,,,,,,,, |
| ASM_129,current_FDA_approved_oligonucleotide_landscape,"2025 FDA TIDES landscape variables are used to represent current modality maturity, approved targets, and continued GalNAc subcutaneous hepatocyte-targeting trends; they do not provide row-level hepatotoxicity measurements.",Keeps the corpus current without treating review landscape data as experimental toxicity data.,medium_high,method_assumption,,,,,,,,,,,,,,, |
| ASM_130,RNA_targeted_therapeutics_platform_logic,"RNA-targeted therapeutic platform records encode broad ASO versus siRNA distinctions: single- versus double-stranded structure, RNase H1 versus Ago2 mechanisms, protein-binding/distribution differences, and delivery requirements.",Adds conceptual platform variables used for interpretation and documentation.,high,method_assumption,,,,,,,,,,,,,,, |
| ASM_131,open_access_freely_downloadable_corpus_boundary,This release only treats open-access or otherwise freely downloadable PDFs available to the developer as directly processed source documents. Other relevant paywalled or unavailable publications may be considered in future database development.,Makes corpus coverage transparent and avoids implying exhaustive access to all literature.,high,method_assumption,,,,,,,,,,,,,,, |
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