Base Editing (ABE8e) for GBA1 c.1093G>A (p.Glu365Lys) in Perinatal-lethal Gaucher disease

Base Editing (ABE8e) via AAV9 delivery is a rationale-driven therapeutic strategy for Perinatal-lethal Gaucher disease targeting the GBA1 c.1093G>A (p.Glu365Lys) variant (Pathogenic, missense variant). The editing system (ABE8e-nSpCas9 (adenine base editor)) converts the pathogenic A back to G on the target strand, restoring the wild-type codon. Target tissue: CNS. Therapeutic goal: Correct the GBA1 c.1448T>G (p.Leu483Arg, L444P) and similar severe loss-of-function alleles (via gene correction or durable gene addition at or functionally equivalent to the native locus) to restore . Risk profile: off-target Medium (bystander bases in editing window), delivery complexity Medium, immunogenicity High (AAV pre-existing immunity).

1. Molecular basis: GBA1 NM_000157.4(GBA1):c.1093G>A (p.Glu365Lys) is classified as Pathogenic (ClinVar variation ID 4299). Molecular consequence: missense variant. Protein change: E365K, E278K, E316K, D179H, D130H, D92H. 2. Epidemiology: Perinatal-lethal Gaucher disease (PLGD) is an extremely rare, most severe end of the type 2 (acute neuronopathic) Gaucher disease spectrum. It typically presents prenatally or in the neonatal period with non-immune hydrops fetalis, collodion-baby/ichthyotic skin, arthrogryposis, respiratory failure, 3. Standard of care: Standard of care for Gaucher disease is based on enzyme replacement therapy (ERT: imiglucerase, velaglucerase alfa, taliglucerase alfa) and substrate reduction therapy (SRT: miglustat, eliglustat), with hematopoietic stem cell transplantation (HSCT) and off-label pharmacologic chaperones (e.g., ambr 4. Pipeline: Multiple ERT and SRT products have full regulatory approval for type 1 and some type 3 Gaucher disease and anchor a mature, multi-billion-dollar global market dominated by type 1 patients (WEB-01, WEB-03, WEB-06, WEB-07, PAPER-06). However, none directly address CNS pathology, and none are labeled f 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 GBA1 c.1093G>A (p.Glu365Lys) with Base Editing (ABE8e); 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. 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.