Objective: CAP-003 is a next-generation gene therapy candidate, comprising a novel brain-tropic capsid paired with hGBA1 cargo, that was developed for administration as a single intravenous (IV) infusion to Parkinson’s disease patients with GBA1 mutations (PD-GBA).

Background: GBA1 gene mutations are the most prevalent genetic risk factor for Parkinson’s disease (PD), with up to 15% of PD patients carrying mutations. These mutations result in reduced function of glucocerebrosidase (GCase), the lysosomal hydrolase enzyme encoded by GBA1, which is associated with the development and spread of Lewy bodies and loss of nigrostriatal dopaminergic neurons, the pathological hallmarks of PD. The central nervous system-targeting and liver/DRG de-targeting profile of CAP-003 offers the potential to safely and stably supplement wild-type GCase protein throughout the brain, enabling long-term disease modification that could slow or stop the progression of PD-GBA with limited treatment burden.

Method: Preclinical studies using patient-derived neurons carrying GBA1 mutations, a mouse model that exhibits both reduced GCase activity and overexpression of alpha-synuclein in the brain, as well as non-human primates (NHPs) were used to characterize the performance of CAP-003 and the hGBA1 gene supplementation strategy.

Results: In both patient-derived cellular and genetic mouse models, AAV administration with hGBA1 cargo resulted in dose-dependent increases in brain GCase protein and activity. Treated mice also showed dose-dependent reductions in glucosylsphingosine (GluSph) levels, a key substrate of GCase. In NHPs, systemic administration of CAP-003 resulted in widespread neuronal transduction that showed marked improvement over wildtype AAV serotypes. Treated NHPs also showed increased brain GCase protein and activity, achieving the target of 30% or higher increase in brain GCase activity that is expected to be disease modifying. CAP-003 was well tolerated, de-targeted from the liver and DRGs, and showed no adverse clinical pathology, immune-related adverse events or adverse histopathology that are frequently associated with higher-dose systemic gene therapies.

Conclusion: CAP-003, targeting IND submission in 1H 2025, aims to achieve disease modifying clinical benefit for PD-GBA patients through a single intravenous dose.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/cap-003-a-cns-targeted-iv-delivered-aav-gene-therapy-developed-for-patients-with-parkinsons-disease-associated-with-gba1-mutations/