Funded Studies
Objective/Rationale:
It is well known that repeated administration of levodopa causes gradual changes in striatal gene expression that eventually result in the development of levodopa-induced dyskinesia in most Parkinson’s disease (PD) patients. But the molecular mechanisms sustaining levodopa-induced dysregulation remain mysterious. Growing evidence suggests that levodopa may cause these sustained changes by tightening the bounds that unite DNA with histones, the protein wrap that keeps DNA tightly packaged into the cell nucleus. This so-called “epigenetic” repression of transcription involves a family of 11 related enzymatic regulators called histones deacetylases. Preliminary findings suggest that gene repression occurs in the dyskinetic brain as a consequence of histone hypoacetylation. In line with this view, clinical evidence indicates that sodium valproate, a weak inhibitor of histone deacetylases that non-selectively enhance histone acetylation, moderates the severity of levodopa-induced dyskinesia in PD patients without altering parkinsonian symptoms.
Project Description:
We will test the hypothesis that blocking a specific combination of histone deacetylases will result in an optimal blockade of the dyskinetic process. To identify which deacetylases (among 11) are the most relevant to interfere with the development of dyskinesia, we will use preclinical models and carry out a viral-mediated loss of function in the stratum. We will then take advantage of a compound library to identify the most promising combination of pharmacological inhibitors to target for treatment.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Preventing the development of levodopa-induced dyskinesia by directly tackling the molecular machinery responsible for the pathological response to levodopa in striatal neurons would represent a great leap in our understanding of dyskinedia and our ability to control their expression.
Anticipated Outcome:
The project will identify a new target for preventing development of levodopa-induced dyskinesia.
Final Outcome
The goal of this program is to provide an effective treatment to reduce/block the aberrant neuroplasticity underlying dyskinesia through tailored pharmacological targeting of histone deacetylase (HDAC). In our study we demonstrated a clear anti-dyskinetic effect obtained by the conditional HDAC6 (a specific histone deacetylase) knock-down in the striatum. The silencing of striatal HDAC6 can improve the motor disabilities caused by L-Dopa-induced dyskinesia (LID) of approximately 60% making this strategy one of the most effective in the treatment of LID. The biggest issue that we faced during this study was the toxicity caused by the AAV9 serotype used in our first experiments. We solved this problem changing the serotype and repeating the experiments. In spite of this, our first observations have been reinforced by the studies conducted with the new serotype, confirming the feasibility to heal dyskinesia by inhibiting the HDAC6 isoform.
In order to provide a clinical-relevant treatment for LID we moved quickly to a preliminary study using an inhibitor (ACY-738) that is selective for the HDAC6. The preliminary data we got so far displayed highly promising results.