Objective/Rationale:
The goal of this project is to determine whether the mTOT insulin sensitizer, MSDC-0160, can both prevent (when given at the same time) or reverse (when given later) the L-DOPA-induced dyskinesia in a pre-clinical model. This is a novel insulin sensitizer that is also in development for the treatment of type 2 diabetes and Alzheimer’s disease.
Project Description:
MSDC-0160 belongs to a recently discovered class of insulin sensitizers that signal through modification of a unique mitochondrial target, leading to reduced activation of the nutrient sensor mTOR. There is substantial evidence that mTOR is over-activated in the striatum during L-DOPA-generated dyskinesia, and that this over-activation plays a causative role. Therefore, MSDC-0160 could potentially be anti-dyskinetic and facilitate treatment with L-DOPA-related medications.
MSDC-0160 will be tested in dyskinesia pre-clinical models (6-hydroxydopamine lesions of the median forebrain bundle combined with L-DOPA administration). To evaluate the effects of MSDC-0160 on abnormal involuntary movements, phosphorylated S6, a downstream target of mTOR, will be measured to assess its activity. We will also measure the potential for neuronal protection with MSDC-0160 treatment, i.e., by preserving tyrosine hydroxylase containing cells.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We anticipate that treatment with MSDC-0160 treatment will both prevent and reverse the negative motor effects of L-DOPA treatment in this pre-clinical model and that the effects of the drug treatment will correlate with its ability to prevent the over-activation of the nutrient sensor mTOR.
Anticipated Outcome:
Positive results in dyskinesia trials would propel the compound into clinical development for PD. If successfully developed for this use, MSDC-0160 would allow more optimal use of L-DOPA-related treatments. Such a treatment would produce an immediate improvement in treatment options for PD patients and may, in the long run, also have the potential to improve disease outcomes.
Final Outcome
A new class of insulin sensitizers, mTOT modulators, is in development for the treatment of diabetes and Alzheimer’s disease. The mechanism of action of these compounds includes a direct effect on mitochondrial metabolism resulting in modulation of a key molecular sensor called mTOR. Since it is known that the dyskinesia caused by levodopa occurs with over-activation of mTOR in the brain and that direct inhibition of the nutrient sensor with toxic compounds can attenuate levodopa-induced dyskinesia, we asked whether the mTOT modulator, MSDC-0160, could impact levodopa-induced dyskinesia in a pre-clinical model. Oral treatment with doses of MSDC-0160 that are effective in clinical trials in diabetic patients and patients with Alzheimer’s disease also decreased levodopa-induced dyskinesia (LID) in the pre-clinical models whether it was given before or after dyskinesia was established. Some models showed a complete reversal of the symptoms that was dependent on the presence of the drug. These results are now being used to design a clinical trial to test the potential of MSDC-0160 to significantly decrease levodopa-induced dyskinesia in patients with Parkinson’s disease.