Study Rationale:
A hallmark of Parkinson’s disease (PD) is the abnormal accumulation of clumps of alpha-synuclein in nerve cells. These improperly folded protein clumps contribute to the symptoms of PD, from tremors to depression. Current therapies, which focus on relieving symptoms by boosting the chemical neurotransmitters normally produced by these nerve cells, offer limited benefits. To target the problem more directly, we will attempt to eliminate alpha-synuclein aggregates using tiny “nanoparticles” to deliver a therapeutic peptide to the cellular machinery that removes misfolded proteins.
Hypothesis:
Using a nanoparticle to deliver a targeted therapeutic could safely and selectively correct alpha-synuclein pathology and minimize brain inflammation.
Study Design:
First we will determine whether our therapeutic nanoparticles will facilitate removal of toxic alpha-synuclein aggregates in isolated nerve cells. We will then turn to a pre-clinical model of PD to determine the lowest single dose of nanoparticles that will safely and effectively reduce the aggregation of alpha-synuclein. We will administer this dose repeatedly to evaluate how the treatment affects the models’ coordination and to assess its long-term impact. After five months, we will examine the brains of the treated models to evaluate whether the therapeutic nanoparticles reduced alpha-synuclein pathology, enhanced cellular clearance mechanisms, minimized brain inflammation, and inhibited neurotransmitter loss.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Nanoparticles coated with therapeutic molecules have been approved by the FDA approved for the treatment of cancer. We therefore expect our therapy to be safe and easily translatable to the clinic. Our approach can also be adapted to the development of additional therapies that target the cellular clearance machinery.
Next Steps for Development:
To prepare our therapy for clinical application, we will first optimize the therapeutic regimen to minimize the number and frequency of injections. We would then perform extensive safety testing in pre-clinical models, followed by a Phase I clinical trial.