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Drug Rescue of PINK1: New Therapeutic Modality for Treating Parkinson’s Disease

Study Rationale:       
Mitochondrial dysfunction has long been linked to Parkinson’s disease. We are investigating a class of drugs that increase the activity of an important mitochondrial quality-control enzyme (PINK1) found in cells affected by Parkinson’s disease. We believe that by increasing the activity of PINK1, we can reduce the rate of cell death and change the trajectory of the disease. Our project designed to provide early evidence that our drugs – and the PINK1 mechanism they target – can provide such a therapeutic benefit.

We believe that administration of our drug will provide significant protection of dopamine neurons in a pre-clinical model of Parkinson’s disease.

Study Design:
The first step in our study will be to ensure that our drugs don’t interfere with the disease model in a way that would make any findings meaningless. We’ll look at the metabolism of the toxin used to induce Parkinson’s-like symptoms when given alongside our drugs. So long as toxin metabolism remains normal, we’ll proceed to the main experiments, which will focus on the drug’s ability to rescue cells from the effects of the toxin. To complete those experiments, we will dose models with our drugs and administer the toxin, then quantify dopamine, dihydroxyphenylacetic acid and homovanillic acid (metabolites of dopamine) in the striatum. We will also count the number of surviving cells in the substantial nigra. If the drugs are providing protection, we would expect to see more cells survive in the drug-treated models vs. controls.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
We believe that the drugs we’re investigating could potentially change the trajectory of Parkinson’s disease, improving patient outcomes and ensuring that they remain responsive to levodopa therapy for longer.

Next Steps for Development:
This study represents an important first step toward validating both the therapeutic mechanism and the new class of drugs. Success would mean we were one step closer to the clinic and, hopefully, one step closer to bringing people with Parkinson’s a disease-altering therapy.

Final Outcome

PINK1 is a protein that prevents cell death by breaking down damaged mitochondria, cell's energy generators. Mitochondrial damage and PINK1 have long been linked to Parkinson's disease (PD). In this study, we investigated whether a drug that activates PINK1 could rescue nerve cells from the damaging effects of a toxin used to model PD. In this study, pre-clinical models received the drug first and the toxin later. We then counted dopamine-producing nerve cells in the substantia nigra, the brain region damaged in PD. We found that our drug protected the substantia nigra from the effects of the toxin, as significantly more dopamine-producing cells survived in the models that received the drug than in those that did not.

October 2015


  • Kevan M. Shokat, PhD

    San Francisco, CA United States

  • Nicholas T. Hertz, PhD

    San Francisco, CA United States

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