Abstract Details

Title Design of Phase 1/2a Study of AAV9-Based Gene Therapy for Parkinson’s Disease with Pathogenic GBA1 Mutations (PROPEL Trial)

Topic Movement Disorders

Presentation(s) P9 - Poster Session 9 (12:00 PM-1:00 PM)

Poster/Presentation
Number 3-013

Objective

Objective: To describe the design of the PROPEL trial of safety, immunogenicity and potential efficacy of a recombinant adeno-associated virus serotype 9 (rAAV9) vector-based gene therapy candidate transducing human GBA1.

Background Background: It is well-established that carriage of GBA1 mutation(s) results in reduced glucocerebrosidase (GCase) activity and substantially increases one’s risk for developing Parkinson’s disease (PD). PD clinical severity correlates with the degree of reduction in GCase activity in blood. Homozygote carriers of GBA1 mutations present with more severe PD than heterozygote carriers, and patients with any GBA1 mutations present with more severe PD than patients with no GBA1 mutations. In Parkinson’s disease with at least one GBA1 mutation (PD-GBA) patients, the delivery of the functional GBA1 gene by rAAV9 directly to the CNS may increase GCase activity, potentially leading to decreased substrate accumulation, halting of disease pathology, and modification of the disease progression.

Design/Methods Methods: PROPEL is a Phase 1/2a randomized, double-blind, sham procedure-controlled, ascending dose study to evaluate the safety of PR001 in patients with PD-GBA (NCT04127578). The study will evaluate two dose levels of PR001 in ascending dose cohorts. A total of 16 patients with moderate to severe PD-GBA will be randomized to receive either PR001, at a low or high dose, administered sub-occipitally intra cisterna magna, or a sham procedure. The primary objective is to evaluate safety and tolerability of PR001. Secondary objectives are to assess pharmacodynamic effects of PR001 on biomarkers such as GCase, glucosylsphingosine, and glucosylceramide in blood and CSF, as well as immunogenicity. Exploratory objectives include the assessment of clinical symptom burden, imaging, functional and structural brain connectivity by MRI and real-world data assessed through digital monitoring.

Results Results: The PROPEL trial is currently open for enrollment.

Conclusions Conclusions: PROPEL will assess dose, safety, tolerability, biomarker and efficacy effects of PR001 and inform its further clinical development.

Authors/Disclosures
Lynne Verselis PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Jeffrey J. Sevigny, MD (F. Hoffmann-La Roche)	Dr. Sevigny has received personal compensation for serving as an employee of Rapport Therapeutics.

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Abstract Details