Combined saposin (prosaposin, PSAP) deficiency

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.

For PSAP c.720+1G>A, a likely pathogenic splice donor variant disrupting prosaposin (PSAP) processing, a splice-switching antisense oligonucleotide (ASO) approach could potentially rescue productive splicing. PSAP encodes the precursor protein that is proteolytically cleaved into four saposin activators (A, B, C, D), each essential for specific lysosomal sphingolipid hydrolases. The c.720+1G>A variant disrupts the exon 6 splice donor, causing exon skipping or intron retention. A splice-switching ASO targeting a nearby cryptic splice site or an exonic/intronic splicing silencer could redirect splicing to restore the canonical transcript.

Prosaposin deficiency is among the most severe lysosomal storage disorders, combining features of Gaucher disease (saposin C), metachromatic leukodystrophy (saposin B), Krabbe disease (saposin A), and Farber disease (saposin D) into a devastating multisystem phenotype. The c.720+1G>A variant disrupts the canonical GT splice donor consensus at the exon 6/intron 6 boundary. Splice-switching ASOs have proven clinically effective for redirecting splicing in other diseases: nusinersen (Spinraza) for SMA, eteplirsen for DMD exon skipping, and milasen (an N-of-1 ASO) for CLN7 disease. For PSAP, an ASO could either block a cryptic splice site that is activated when the canonical donor is lost (forcing exon inclusion via an alternative mechanism) or target an exonic splicing silencer to enhance inclusion of the upstream exon via remaining weak splice signals. Even partial restoration of PSAP expression (~10-20% of normal) may provide clinically meaningful saposin levels given the enzymatic amplification in lysosomal catabolism.

Combined PSAP deficiency is extremely rare (fewer than 20 reported cases), making clinical trial design virtually impossible. The clinical course is typically fatal in infancy, leaving almost no time for therapeutic intervention. Splice-switching ASO design for this specific variant is entirely theoretical — no preclinical studies exist. The ASO must reach multiple affected organ systems (CNS, liver, spleen), requiring either intrathecal + systemic delivery or a platform with broad tissue distribution. Even if splicing is partially rescued, the degree of functional prosaposin restoration needed to ameliorate the combined deficiency of four saposin activators is unknown. Each saposin has different tissue-specific requirements, and partial restoration may correct some but not all sphingolipid pathways. The N-of-1 milasen precedent is encouraging for ultra-rare splice variants, but required extensive personalized development.