Study Rationale:
Numerous publications have linked the family of epigenetic enzymes known as HDACs (histone deactylases) to the underlying pathology of Parkinson's. This study will test the efficacy of Rodin's selective HDAC inhibitors in improving the impaired motor dysfunction in two models of Parkinson's disease (PD). These compounds may also have impact on cognitive dysfunction associated with PD.
Hypothesis:
Specific HDAC inhibitors will improve brain pathology and symptoms in two models of Parkinson's disease, and these results will be used to support the case for testing in clinical trials in humans.
Study Design:
Two models of Parkinson's will be used to test Rodin's HDAC inhibitors: the MPTP model, which uses a chemical toxin that results in Parkinson's pathology, and a transgenic model known as the A53T synuclein model, which overexpresses a toxic form of a key protein linked to Parkinson's. In both cases, the models will be treated for 14 days with Rodin HDAC inhibitors in an attempt to stabilize or improve symptoms in the mice. Brain sections will be analyzed for expression of key molecules and levels of gene expression to understand the underlying mechanism of the drug's actions.
Impact on Diagnosis/Treatment of Parkinson's Disease:
We are attempting to develop drugs that take a new approach to improving the symptoms and underlying damage that has occurred in Parkinson's patient's brains.
Next Steps for Development:
If this study is successful, we will test the HDAC inhibitor compounds further in these and/or other models of Parkinson's disease to help pick the best compounds as clinical candidates. We will then perform the requisite safety and related studies to move the chosen compounds forward toward clinical trials in humans.
Final Outcome
We continued to develop selective HDAC inhibitors -- drugs that enhance synaptic function -- for the treatment of Parkinson's disease dementia, progressing toward selection of a leading drug candidate in 2017.
It is known that class I selective HDAC inhibitors, such as CI-994 cancer therapeutic, can improve learning and memory by turning on genes that make synaptic proteins in the brain. We have been focusing on creating improved, more powerful HDAC inhibitors that are just as effective but much less toxic. We have developed drugs with low toxicity toward blood cells that remain effective in the brain. At non-toxic levels, these drugs activate genes associated with synaptic function, increase dendritic spine density and improve long-term potentiation (both of which lead to memory improvement) in pre-clinical models of memory loss and in healthy models.
These results suggest that our HDAC inhibitors will enhance learning and memory and could be used to improve cognition in people with Parkinson's disease.
Presentations & Publications
None at this time.