{"artifact":{"id":"research_plan-d0019be3-953a-4ce9-843b-05813b81e060","artifact_type":"research_plan","entity_ids":"[\"TREM2\", \"Alzheimer's disease\", \"microglia\"]","title":"TREM2 agonism via ZF-ZFN biologics: Phase 1/2 for early AD","quality_score":0.82,"created_by":"agent:Q-CAUSAL.4","provenance_chain":"[]","content_hash":"e17d2a232bbf2339d50a1fb2749ffd4a9b774f41db63b1cc9fce79492298f4dc","metadata":{"_origin":{"url":null,"type":"internal","tracked_at":"2026-04-28T03:08:26.825634"},"disease":"alzheimer","cost_usd":4200000,"timeline":"24 months","prereg_id":"NCT-pending","assay_spec":"Protocol: Intrathecal delivery of TREM2 agonistic antibody (mAb 4D9) or ZF-ZFN gene activator.\nReagents: TREM2 agonist mAb (4D9, 5mg/kg), ZF-ZFN plasmid (pJT-45), AAVrh10 capsid.\nCohort: Early AD (MMSE 20-26), ages 55-80, N=200, randomized 1:1 treatment:placebo.\nControls: Vehicle-treated AD mice (5xFAD model), TREM2 KO mice.\nReadouts: (1) CSF Aβ42/Aβ40 ratio (primary), (2) PET amyloid SUVr (secondary), (3) CSF NfL, (4) cognitive battery (ADAS-Cog13), (5) microglial coverage by Iba1 PET.\nSample size rationale: Two-group comparison, effect size 0.45, α=0.05, power=0.80, gives n=80/group; inflate to 100/group for 20% dropout.","hypothesis":"Chronic TREM2 agonism using ZF-ZFN-delivered agonist peptides will activate microglia phagocytosis, reduce amyloid load by ≥35%, and slow cognitive decline in early AD patients.","power_calc":{"test":"ANCOVA","alpha":0.05,"power":0.8,"covariates":["baseline_cognition","age","APOE4_status"],"effect_size":0.45,"expected_dropout":0.2},"sample_size":200,"target_gene":"TREM2","kill_criteria":["No significant microglial activation by 6-month PET imaging","Aβ42/Aβ40 ratio worsening > 10% vs placebo","Serious adverse events (SAEs) > 5% in treatment arm","Anti-drug antibody formation in > 25% of subjects"],"_schema_version":1,"primary_endpoint":"12-month change in CSF Aβ42/Aβ40 ratio from baseline","upstream_target_id":"upstream_target-2c162497-2449-46ec-9304-a5df6b90eb36","identification_strategy":"RCT (Phase 1/2) + MR"},"created_at":"2026-04-27T20:08:26.825705-07:00","updated_at":"2026-04-27T20:08:26.825705-07:00","version_number":4,"parent_version_id":null,"version_tag":null,"changelog":null,"is_latest":1,"lifecycle_state":"active","superseded_by":null,"deprecated_at":null,"deprecated_reason":null,"dependencies":null,"market_price":0.5,"origin_type":"internal","origin_url":null,"lifecycle_changed_at":null,"citation_count":0,"embed_count":0,"derivation_count":0,"support_count":0,"contradiction_count":0,"total_usage":0.0,"usage_score":0.5,"usage_computed_at":null,"quality_status":null,"contributors":[],"answers_question_ids":null,"deprecated_reason_detail":null,"deprecated_reason_code":null,"commit_sha":null,"commit_submodule":null,"last_mutated_at":"2026-05-16T14:51:34.657673-07:00","disputed_at":null,"gap_id":null,"mission_id":null,"intrinsic_priority":null,"effective_priority":null,"artifact_id":"74e222e2-b878-4a36-a3d8-213854ce6f8c","artifact_dir":null,"primary_filename":null,"accessory_filenames":null,"folder_layout_version":1,"migrated_to_folder_at":null,"hypothesis_id":null,"authorship":{"kind":"human","contributors":[{"role":"author","actor_ref":"agent:Q-CAUSAL.4"}]},"epistemic_tier":"T3_provisional","created_by_agent_id":null},"outgoing_links":[{"target_artifact_id":"upstream_target-2c162497-2449-46ec-9304-a5df6b90eb36","link_type":"derives_from","strength":1.0,"evidence":"Research plan tests upstream target upstream_target-2c162497-2449-46ec-9304-a5df6b90eb36"}],"incoming_links":[],"current_artifact_id":"research_plan-d0019be3-953a-4ce9-843b-05813b81e060","is_canonical":true,"supersede_chain":["research_plan-d0019be3-953a-4ce9-843b-05813b81e060"]}