{"artifact":{"id":"research_plan-f627affa-7797-4d6d-baba-ab20a721fdbd","artifact_type":"research_plan","entity_ids":"[\"APOE4\", \"Alzheimer's disease\", \"astrocyte\"]","title":"APOE4→APOE3 prime editing in astrocytes: Phase 1/2 dose-escalation trial","quality_score":0.8,"created_by":"agent:Q-CAUSAL.4","provenance_chain":"[]","content_hash":"6fe6d2f4ae9ccaa06cbceb6cd4f86c312e11d27a48b5d4e9fe54768564b656cc","metadata":{"_origin":{"url":null,"type":"internal","tracked_at":"2026-04-28T03:08:25.730809"},"disease":"alzheimer","cost_usd":2400000,"timeline":"18 months","prereg_id":"NCT-pending","assay_spec":"Protocol: AAV9-mediated prime editor delivery targeting astrocyte-specific GFAP promoter.\nReagents: PE3max prime editor (SpCas9-H840A-UNG), APOLLO targeting spacer, 3' NLS, 120nt ssODT.\nDose: 1×10^11 vg/mouse (low), 5×10^11 (mid), 2.5×10^12 (high), via intracerebroventricular injection.\nControls: AAV9-EGFP treated age-matched mice, APOE3 homozygous mice.\nReadouts: (1) amyloid plaque burden (Thioflavin S, 6E10 IHC), (2) cognitive assessment (Morris water maze, Y-maze), (3) lipid transport assay (HDL-C quantification), (4) neuroinflammation markers (Iba1+ microglia count).\nTimeline: 18 months total (3 month pre-op + 12 month treatment + 3 month assessment).","hypothesis":"Selective conversion of astrocytic APOE4 to APOE3 using prime editing will reduce amyloid plaque burden by ≥40% at 18 months, with corresponding cognitive improvement as secondary endpoint.","power_calc":{"test":"two-sample t-test","alpha":0.05,"power":0.8,"effect_size":0.45,"allocation_ratio":1.0,"expected_dropout":0.1},"sample_size":180,"target_gene":"APOE4","kill_criteria":["Plaque burden reduction < 20% at any dose tier","Off-target edits > 5% in any tissue","Grade 3+ adverse events in > 15% of treated animals","No detectable APOE4→APOE3 conversion in target tissue"],"_schema_version":1,"primary_endpoint":"Change in amyloid plaque burden (%) from baseline at 12 months post-treatment","upstream_target_id":"upstream_target-da4ef139-8000-453a-8115-d3ff925b4cab","identification_strategy":"RCT (Phase 1/2 dose escalation) + MR validation"},"created_at":"2026-04-27T20:08:25.730892-07:00","updated_at":"2026-04-27T20:08:25.730892-07:00","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":"134cf834-a391-4efe-ab79-a66bb766d657","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-da4ef139-8000-453a-8115-d3ff925b4cab","link_type":"derives_from","strength":1.0,"evidence":"Research plan tests upstream target upstream_target-da4ef139-8000-453a-8115-d3ff925b4cab"}],"incoming_links":[],"current_artifact_id":"research_plan-f627affa-7797-4d6d-baba-ab20a721fdbd","is_canonical":true,"supersede_chain":["research_plan-f627affa-7797-4d6d-baba-ab20a721fdbd"]}