NM_000157.4(GBA1):c.1504C>T (p.Arg502Cys)

For the severe neuropathic forms of Gaucher disease (types 2 and 3, including perinatal-lethal), AAV-mediated GBA1 gene therapy targeting the CNS is the most promising emerging approach, as current enzyme replacement therapy (ERT, imiglucerase/velaglucerase) does not cross the blood-brain barrier. The p.Arg502Cys variant is associated with severe disease and produces a misfolded glucocerebrosidase with severely reduced catalytic activity. AAV gene therapy delivering functional GBA1 to neurons and macrophage-lineage cells could address both the visceral and neurological components of the disease.

Gaucher disease results from biallelic GBA1 mutations causing deficiency of glucocerebrosidase (GCase), leading to accumulation of glucosylceramide and glucosylsphingosine in lysosomes of macrophages and neurons. The p.Arg502Cys substitution (historically R463C in older nomenclature) disrupts a conserved residue in domain III of GCase involved in protein stability, resulting in ER retention and degradation via ERAD. Prevail Therapeutics (acquired by Eli Lilly) developed PR001 (LY3884961), an AAV9 vector delivering GBA1 via intracisternal injection, initially for GBA1-associated Parkinson disease and neuronopathic Gaucher disease. A Phase 1/2 trial (NCT04411654) was initiated. Preclinical studies in Gba1 knock-in and conditional knockout mice showed that AAV-GBA1 delivery to the CNS reduced glucosylsphingosine accumulation, improved neuroinflammation markers, and extended survival in severe models. For visceral disease, ERT remains the standard, but the perinatal-lethal form is refractory to ERT due to fulminant neurodegeneration.

Perinatal-lethal Gaucher disease (type 2) is typically fatal within the first 2 years of life, creating an extremely narrow treatment window. Prenatal or neonatal gene therapy delivery would be needed, which poses extreme technical and ethical challenges. The p.Arg502Cys variant in homozygosity or in compound heterozygosity with other severe alleles (e.g., L444P) produces the most severe phenotypes where neurodegeneration may be too advanced at birth for postnatal intervention. AAV-mediated gene therapy must transduce both neurons and microglia/macrophages — the primary storage cells — and AAV9 transduces neurons more efficiently than myeloid cells, potentially leaving the macrophage compartment undertreated. Anti-AAV9 maternal antibodies could neutralize the vector in neonatal patients. The PR001 trial focused primarily on GBA-Parkinson disease, and specific efficacy data for perinatal Gaucher are not available.