miRNA-based Therapy for Parkinson's Disease
Therapeutics Development Initiative -- Academic Track, 2008
A central pathological finding associated with PD is the presence of distinctive, abnormal aggregates in brain cells typically lost in PD, termed dopamine neurons. These aggregates are composed of defective proteins including one called alpha-synuclein. Furthermore, genetic mutations in alpha-Synuclein can lead to PD, and this appears to be the result of excessive accumulation of the protein. In this grant, we propose a novel approach to reducing the level of alpha-Synuclein.
To reduce the accumulation of alpha-synuclein, we will take advantage of a recently described, unusual cellular mechanism that normally inhibits the production of alpha-synuclein. Surprisingly, this mechanism is based on short strands of RNA that serve to fine-tune the expression of many proteins. Because we will take advantage of this normal pathway that inhibits alpha-synuclein, the project does not require us to design artificial compounds that may do so. The alpha-synuclein inhibitors that we will generate can be delivered using existing gene therapy vectors. Thus, if they prove effective in cell and animal models of PD, these inhibitors could be directly taken towards human clinical trial-enabling studies.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
There is a critical need for the development of therapies that prevent or reverse the progression of PD, as no currently available drugs do so. The goal of this project is to develop novel therapies that can be taken forward to clinical trials
Our current understanding of the ‘naturally occurring’ inhibitors of alpha-Synuclein expression is limited. The first aim of this project is to identify which RNAs play a central role in regulating the expression of alpha-synuclein. Subsequently, in the second Aim, we will take this forward to determine whether these naturally-occurring inhibitors of alpha-synuclein expression are effective in treating disease models. Thus, the goal is to learn both about the normal function and basic science of alpha-synuclein, as well as about the clinical value of these inhibitors in animal models.
INTERIM PROGRESS REPORT
A number of candidate micro RNAs with the ability to reduce alpha-synuclein in cell culture models have been identified. These candidates will now be tested in an in vivo alpha-synuclein model.
RNA interference (RNAi) affords a potential approach to reduce the accumulation of aSynuclein, which is hypothesized to directly or indirectly be involved in PD pathology. MiRNAs are short endogenous RNA species that mediate RNAi to negatively regulate the expression of many genes, including aSynuclein. Although synthetic RNAi can be achieved with artificial siRNA species, there is evidence that siRNA is more toxic than miRNA in vivo. Furthermore, a precise understanding of the normal miRNA regulation of aSynuclein within midbrain dopamine neurons may greatly facilitate the generation of effective RNAi therapeutics targeted at aSynuclein.
Associate Professor at Columbia University Medical Center
Location: New York, New York, United States