Abstract
Background: Gaucher disease (GD) is a rare autosomal recessive disorder caused by GBA1 mutations, leading to deficient glucocerebrosidase (GCase) activity and accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (Lyso-GL1), resulting in multisystemic involvement. Current treatments—enzyme replacement therapy (ERT) and substrate reduction therapy (SRT)—are limited by delayed diagnosis, life-long administration, high cost, adverse effects, and poor adherence. LY-M001 is a novel rAAV8-based gene therapy delivering a codon-optimized GBA1 transgene under a liver-specific promoter to express a modified GCase (GCaseLY). This investigator-initiated trial evaluates the safety and therapeutic potential of LY-M001 in type I GD.
Methods: This single-center, single-arm, dose-escalation study was conducted at the First Affiliated Hospital of Zhejiang University School of Medicine (Hangzhou, China) to evaluate the safety and preliminary efficacy of LY-M001, an AAV8-based GBA1 gene therapy, in adults with type I Gaucher disease. Eligible participants (aged 18–60) had confirmed GBA1 mutations, no prior use of GCase inhibitors, and low anti-AAV8 neutralizing antibody titers (≤1:10). After one week of prophylactic prednisone (1 mg/kg/day), participants received a single intravenous infusion of LY-M001 at either 5×10¹² vg/kg (Cohort 1, n=1) or 1.5×10¹³ vg/kg (Cohort 2, n=2). Primary endpoints included treatment-related adverse events (AEs), changes in ALT/AST, and development of anti-capsid antibodies over 12 months. (ClinicalTrials.gov: NCT06162338)
Results: Between November 2023 and August 2024, six patients were screened, and three females were enrolled. After a median follow-up of 76 weeks (IQR 69–85), all participants showed increased peripheral GCase levels and activity. Both participants in cohort 2 showed reduced peripheral Lyso-GL1 level. The sole participant in cohort 1 also showed reduced Lyso-GL1 level after combining ERT therapy. Hemoglobin and platelet counts improved in Cohort 2, and both patients remained off ERT for 19 months. Liver and spleen volumes decreased within 6 months across all patients. No serious adverse events (SAEs) were reported. The sole Cohort 1 patient experienced mild infusion-related symptoms (diarrhea, abdominal pain, headache), managed with symptomatic treatment. In Cohort 2, one patient had transient ALT elevations (peak 96 IU/L) and delayed mild elevation (ALT 73 IU/L), managed with oral tacrolimus. The other participant reported transient left lower lip numbness, also managed with symptomatic treatment. All patients developed anti-AAV8 neutrilizing antibodies post-infusion. Three screened patients were excluded due to high neutralizing antibody titers. Pharmacodynamic data collection is ongoing.
Conclusion: This pilot study suggests that LY-M001 is well tolerated up to 21 months post-infusion, with encouraging biochemical and clinical responses observed in the medium-dose cohort. LY-M001 holds potential as a promising gene therapy alternative to current GD treatments, addressing key unmet clinical needs.
