NM_002778.4(PSAP):c.1A>G (p.Met1Val)

Base Editing (BE4max) via AAV9 delivery is a rationale-driven therapeutic strategy for Combined saposin (prosaposin, PSAP) deficiency targeting the PSAP c.1A>G (p.Met1Val) variant (Pathogenic, missense variant, initiator_codon_variant). The editing system (BE4max (cytosine base editor)) converts the pathogenic C to T (or G to A on the target strand), restoring the wild-type codon. Target tissue: CNS. Therapeutic goal: Correct loss-of-function PSAP variants in CNS and visceral tissues to restore saposin A–D activity and normalize lysosomal sphingolipid metabolism, aiming for durable disease modification or cure.. Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity High (AAV pre-existing immunity).

1. Molecular basis: PSAP NM_002778.4(PSAP):c.1A>G (p.Met1Val) is classified as Pathogenic (ClinVar variation ID 860182). Molecular consequence: missense variant, initiator_codon_variant. Protein change: M1V. 2. Epidemiology: Extremely rare, with only a few reported infants with combined saposin (prosaposin, PSAP) deficiency worldwide; presentations are typically neonatal or very early infantile with severe neurovisceral storage disease and death within months. Overall PSAP-related spectrum (isolated saposin deficiencies 3. Standard of care: No disease-specific approved therapy for combined PSAP deficiency. Management is supportive and palliative, focusing on seizure control, respiratory support, and nutritional and palliative care. For related saposin B or C deficiencies that mimic metachromatic leukodystrophy or Gaucher disease, hemat 4. Pipeline: No interventional clinical trials targeting PSAP deficiency or combined saposin deficiency were identified. Gene therapy experience exists for analogous lysosomal storage diseases (e.g., lentiviral ARSA gene therapy for metachromatic leukodystrophy and gene-addition/CRISPR approaches for other lysos 5. CBE clinical validation: BE4max (Koblan et al. 2018) is the gold-standard cytosine base editor. Multiple CBE programs are in clinical development for liver and hematologic targets.

1. No published data specifically correcting PSAP c.1A>G (p.Met1Val) with Base Editing (BE4max); 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. 4. Delivery to CNS tissue remains a major translational bottleneck. Current vectors have limited transduction efficiency in these compartments. 4. Long-term durability, off-target genome-wide effects, and immunogenicity in the target patient population require thorough preclinical and clinical evaluation.