Evaluation of “PDRepair,” a Novel Neuroprotective and Neurorestorative Therapeutic for GBA1-associated Parkinson’s Disease

Study Rationale: Mutations in the GBA1 gene, which encodes an enzyme called GCase, is the strongest genetic risk factor for Parkinson’s Disease (PD) and most often results in the production of GCase with decreased activity and abnormal toxic signaling. We have developed a therapy that both restores the function of the mutated GCase enzyme and enhances overall GCase signaling, thereby targeting a broad number of different GBA1 mutations associated with PD. By combining this therapeutic with the clinically validated neurorestorative factor GDNF, we have produced a combined neuroprotective and neurorestorative therapy tailored toward treatment of early symptomatic GBA1-associated PD.

Hypothesis: We hypothesize that delivery of GDNF along with GCase cofactors will prevent GCase misfolding, enhance GCase signaling, ameliorate downstream neuropathologies and improve motor and behavioral abnormalities in preclinical models of GBA1-associated PD.

Study Design: We will use a minimally invasive therapeutic device, encapsulated cell based biodelivery (ECB), to administer either GDNF or different GCase cofactors in two different GBA1-associated preclinical PD models. The treatments will be compared for their ability to enhance the activity of mutated and nonmutated GCase in the brain. The most efficient GCase-stimulating factors will be combined with GDNF in a single ECB therapy and tested for their ability to attenuate the aggregation of alpha-synuclein and the development of other neuropathologies as well as their ability to rescue the PD-like motor and cognitive dysfunction that develops in the GBA1 models.

Impact on Diagnosis/Treatment of Parkinson’s disease: PD is a heterogenous group of disorders and the development of therapies targeted to specific disease subtypes offers great promise. PDRepair—a unique, combination therapeutic that presents both neuroprotective and neurorestorative factors specifically tailored for GBA1-associated PD—has the potential to become the first disease-modifying therapy for PD.

Next Steps for Development: The next step will be to perform preclinical toxicology studies with PDRepair and then to file an IND application for clinical translation.