A Rigorous Conceptual Framework for GenLipid-X: Precision Dual Base Editing of PCSK9 and LDLR with PPAR\( \alpha \) Agonism in Familial Hypercholesterolemia -- Advanced Sensitivity, Molecular Docking, and Safety Integration

Familial hypercholesterolemia (FH) affects ∼1 in 250 individuals worldwide (prevalence∼400 per 100,000) (1), driven by PCSK9 gain-of-function and LDLR loss-of-functionmutations that elevate LDL-C and ASCVD risk (2). GenLipid-X proposes a dual-modalityapproach: (1) High-fidelity ABE/CBE multiplex editing of PCSK9 (c.179G>A, p.Gly60Asp)and LDLR (c.81C>T, p.Cys27Tyr) via eSpCas9, with safety factor αsafety = 0.001; (2)PPARα agonist conjugate (docking affinity -8.2 kcal/mol vs. -8.1 kcal/mol fenofibric acid;PDB: 6LX4) (11). ApoE-enhanced LNPs (t1/2 > 24 h) support >3,500 LDLR variantsvia sgRNA libraries (16). Rigor includes PK/PD ODEs, SciPy simulations, Sobol analysis(Sδg,η = 0.12; Sη(t = 30) = 0.53, Sδg(t = 730) = 0.47), Bayesian inference (Beta(12,6),pˆ = 0.67, 95% CrI [125, 135] mg/dL for LDLss), and MC-UQ (σ2[LDL] = 6 mg/dL2) (13).GenLipid-X forecasts 70–80% LDL-C reduction and 45–55% TG mitigation, exceedingPCSK9 inhibitors (50–70%) (4) and fibrates (40–60%) (10), with one-time dosing likeVERVE-101 (up to 55%) (12).