Codevelopment of Small-molecule Regulators of Miro1 for the Treatment of Parkinson’s Disease and a GLP Clinical Biomarker Assay

Study Rationale:    
The mitochondrial protein Miro1 is elevated in more than 90% of all Parkinson’s disease (PD) patients of both genetic and sporadic forms. The high level of Miro1 is a pathogenic driving factor in PD disease progression. AcureX has discovered that antagonists of a specific calcium-channel family decrease harmful Miro1 levels down to healthy levels. AcureX is advancing a new class of calcium-channel antagonists as disease modifying therapies for the treatment of PD.  To accelerate the development these new therapies, AcureX is developing a biomarker assay measuring Miro1 levels outside the central nervous system in white blood cells.

Hypothesis:
Do selective calcium-channel antagonists lower Miro1 levels to that of healthy individuals and slow PD disease progression?  Does the level of Miro1 in white-blood cells (PBMCs) reflect the elevated levels of Miro1 in the PD brain? Do drugs that lower Miro1 levels in PBMCs also cause Miro1 reduction in the brain, enabling PBMC Miro1 levels to serve as a PD clinical biomarker of drug effect?

Study Design:
The AcureX Therapeutics team will study the effect of drug on Miro1 levels after the genetic suppression of each calcium channel in iPSC dopaminergic neurons.  With this information, the team will synthesize compounds with a selectivity profile defined by these calcium channel knock-down studies.  The best compounds will be tested in an -synuclein based animal model of PD.  We will also determine if there is a measurable Miro1 defect in the white-blood cells of PD patients and if the Miro1 level in white-blood-cells is a translational biomarker of drug effect in the CNS of PD patients.

Impact on Diagnosis/Treatment of Parkinson’s disease:
This project advances in parallel, both a clinical biomarker and diagnostic for Parkinson’s disease in conjunction with a new therapy for the treatment of PD.  Therapies which slow PD disease progression benefit significantly from having a clinical biomarker to monitor target engagement and disease progression to guide their development.

Next Steps for Development:
The outcome of this grant is the nomination of a drug candidate for IND-enabling pharm-tox studies.  Upon completion of the IND-enabling pharm-tox studies, the therapy will immediately begin Phase 1 clinical studies, testing its ability to restore healthy Miro1 levels in PD subjects.