Prenatal-onset spinal muscular atrophy with congenital bone fractures

PERT (Prime Editing-mediated tRNA Rewriting) or ABE/CBE stop-codon reversion via Dual-AAV delivery is a rationale-driven therapeutic strategy for Prenatal-onset spinal muscular atrophy with congenital bone fractures targeting the ASCC1 c.382C>T (p.Arg128Ter) variant (Pathogenic, nonsense, non-coding transcript variant). The editing system (PEmax for PERT, or ABE8e/BE4max if the stop codon is revertible via single transition) PERT rewrites a redundant endogenous tRNA into a suppressor tRNA that reads through the premature stop codon, restoring full-length protein. Alternatively, if the nonsense mutation arose from a transition (e.g., CAG→TAG), ABE or CBE can directly revert the stop codon. Target tissue: CNS. Therapeutic goal: Restore functional ASCC1 (and/or SMN1-SMN2 axis) to prevent motor neuron degeneration and congenital bone fractures in prenatal-onset SMA phenotypes.. Risk profile: off-target Low (prime editing) to Medium (base editing bystanders), delivery complexity Medium, immunogenicity High.

1. Molecular basis: ASCC1 NM_001198800.3(ASCC1):c.382C>T (p.Arg128Ter) is classified as Pathogenic (ClinVar variation ID 801334). Molecular consequence: nonsense, non-coding transcript variant. Protein change: R156*, R128*, R150*, R89*. 2. Epidemiology: Executed all subtasks assigned to web in plan.jsonl: (1) characterized SMA phenotypes and care pathways with focus on prenatal/infantile onset using Orphanet-style disease overviews, payer policies and SMA newborn-screening practice data; (2) quantified severity and economic/market aspects via HTA r 3. Standard of care: High-cost disease-modifying SMA therapies (nusinersen, onasemnogene abeparvovec, risdiplam) with intensive supportive respiratory and orthopedic care; no approved therapy specifically for ASCC1-related SMABF2. 4. Pipeline: Executed all subtasks assigned to web in plan.jsonl: (1) characterized SMA phenotypes and care pathways with focus on prenatal/infantile onset using Orphanet-style disease overviews, payer policies and SMA newborn-screening practice data; (2) quantified severity and economic/market aspects via HTA r 5. ABE clinical validation: ABE8e (Richter et al. 2020, Nat Biotechnol) achieves ~1.7x higher editing efficiency than ABE7.10. VERVE-101 demonstrated first-in-human LNP-ABE liver editing with 55-66% PCSK9 reduction (Raal et al. 2025, NEJM). Beam Therapeutics is advancing multiple ABE programs.

1. No published data specifically correcting ASCC1 c.382C>T (p.Arg128Ter) with PERT (Prime Editing-mediated tRNA Rewriting) or ABE/CBE stop-codon reversion; strategy is based on general principles and must be validated preclinically. 2. PAM availability and bystander base analysis for the specific genomic context have not been performed. If no canonical NGG PAM positions the target within the editing window, PAM-flexible variants (SpRY) may be needed. 3. Dual-AAV delivery requires intein-mediated protein reconstitution with lower efficiency than single-AAV. Pre-existing AAV immunity in the patient population may limit eligibility. 4. Delivery to CNS tissue remains a major translational bottleneck. Current vectors have limited transduction efficiency in these compartments. 5. Long-term durability, off-target genome-wide effects, and immunogenicity in the target patient population require thorough preclinical and clinical evaluation.