NM_002778.4(PSAP):c.720+1G>A

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.