Study Rationale: Studies in preclinical models of Parkinson’s disease (PD) and in postmortem PD brains suggest that a signaling pathway that is switched on by activation of a protein called phosphatidylinositol 3-kinase (PI3K) plays a role in PD pathogenesis. This same pathway is overactive in a handful of adult and pediatric brain cancers. Clinical trials are currently assessing the effectiveness of paxalisib, a drug that can enter the brain and inhibit PI3K, in treating these cancers. We propose to determine whether paxalisib can be repurposed for the treatment of PD.
Hypothesis: We hypothesize that paxalisib, an anticancer drug that targets the PI3K pathway and can penetrate into the brain, can be repurposed to modify the course of PD, interfering with disease progression.
Study Design: Paxalisib will be tested in a preclinical PD model that expresses a mutated form of the human alpha-synuclein protein. We will also administer the drug to control, non-mutant animals. Paxalisib will be given orally for 28 days at a dose of 20mg/kg/day. We will assess the potential impact of paxalisib on lifespan and on disease biomarkers related to alpha-synuclein in the brain and cerebrospinal fluid, through examination of biochemistry, gene expression and pathology.
Impact on Diagnosis/Treatment of Parkinson’s disease: We anticipate that the drug will slow or inhibit disease progression.
Next Steps for Development: If successful, this study will provide the groundwork to perform a clinical trial for paxalisib repurposed for the treatment of PD.