Abstract Details

Title Systemic AAV Gene Therapy Using a CNS-targeted Engineered Capsid Significantly Increases GCase Activity to Support the Potential Treatment of PD-GBA

Topic Movement Disorders

Presentation(s) S37 - Movement Disorders: Clinical Trials (2:12 PM-2:24 PM)

Poster/Presentation
Number 007

Background Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the United States with no approved disease modifying treatments to date. GBA1 gene mutations are the most significant risk factor for PD, with current evidence suggesting up to 15% of PD patients carry mutations.

Objective

Capsida has developed a next-generation gene therapy candidate (CAP-003) for administration as a single intravenous (IV) infusion to Parkinson’s disease patients with GBA1 mutations (PD-GBA).

Design/Methods CAP-003 is a PD-GBA therapy utilizing a novel AAV capsid engineered by directed evolution with the goal of delivering functional human GBA1 broadly across the CNS and providing a permanent source of the GCase protein to enable long-term disease modification that could slow or stop the progression of PD-GBA.

Results Studies in a glucocerebrosidase (GCase) loss-of-function mouse model showed systemic AAV administration of hGBA1 resulted in increased GCase activity in the brain and significant reductions in glycosphingolipid species that likely contribute to alpha-synuclein pathology. In NHPs, systemic administration of CAP-003 resulted in widespread neuronal transduction, including disease relevant brain regions such as the substantia nigra, caudate, and putamen. These levels of transduction show marked improvement over wildtype AAV serotypes and resulted in significantly increased GCase activity that is expected to normalize GCase activity in the PD-GBA patient population. Analysis of clinically relevant biomarkers showed increases in GCase protein and activity and reductions in glucosylsphingosine, a key GCase substrate. CAP-003 was found to be well tolerated, de-targeted from the liver and DRGs, and lacking clinical pathology or immunogenicity findings associated with higher-dose systemic gene therapies.

Conclusions Targeting a 1H 2025 IND filing, CAP-003 is being advanced with the goal of achieving disease modifying clinical benefit for patients with PD-GBA through a convenient single dose IV administration.

Authors/Disclosures
Reed Ressler, PhD PRESENTER	Dr. Ressler has received personal compensation for serving as an employee of Capsida Biotherapeutics.
Kim McDowell, PhD	Dr. McDowell has received personal compensation for serving as an employee of Capsida Biotherapeutics.
Brandon G. Wheeler	Mr. Wheeler has received personal compensation for serving as an employee of Capsida.
Shelby Thomas, MS	Ms. Thomas has received personal compensation for serving as an employee of Capsida Biotherapeutics .
Lubov S. Grigoryeva, PhD	Dr. Grigoryeva has received personal compensation for serving as an employee of Capsida Biotherapeutics.
Alexander Armendariz	Mr. Armendariz has nothing to disclose.
maeve flynn	Ms. flynn has received personal compensation for serving as an employee of Capsida Biotherapeutics .
Hari Acharya, PhD	Dr. Acharya has received personal compensation for serving as an employee of Capsida.
Paul Denis	Mr. Denis has received personal compensation for serving as an employee of Capsida Biotherapeutics. Mr. Denis has stock in Amgen Inc..
Pasha Tchourilov	Mr. Tchourilov has received personal compensation for serving as an employee of Capsida Biotherapeutics. Mr. Tchourilov has stock in Capsida Biotherapeutics.
Swati Tole, MD	Dr. Tole has received personal compensation for serving as an employee of Capsida Biotherapeutics. Dr. Tole has stock in Capsida Biotherapeutics. Dr. Tole has stock in Roche.
Nick Goeden, PhD	Dr. Goeden has received personal compensation for serving as an employee of Capsida Biotherapeutics . Dr. Goeden has stock in Capsida Biotherapeutics . Dr. Goeden has received intellectual property interests from a discovery or technology relating to health care.
Nicholas Flytzanis, PhD	Dr. Flytzanis has received personal compensation for serving as an employee of Capsida Biotherapeutics, Inc.. Dr. Flytzanis has received intellectual property interests from a discovery or technology relating to health care.

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