Analysis of a viral non-coding RNA as a novel therapeutic in a chronic MPTP pre-clinical model of Parkinson's disease and its mechanism of mitochondrial protection
MJFF Research Grant, 2011
Promising Outcomes of Original Grant:
Previously, we identified a viral RNA which could act as a novel protective agent in models of PD, when delivered before experimental damage to neurons of the substantia nigra (SN). We observed that this viral RNA was protective when delivered directly to the brain, but also when it was delivered by injection into the bloodstream. In both cases, the viral RNA inhibited neuronal cell death. Neuronal damage in PD, however, is often much more long-term and chronic compared to the experimental damage induced in pre-clinical models of PD and any delivery of this type of therapeutic would need to be administered after the initial features of PD have become manifest. Therefore, we have tested whether this viral RNA could also provide protection when delivered shortly after the start of experimental damage in a more chronic model of PD. Our work has now shown that the novel viral RNA does indeed protect against neuronal cell death when delivered shortly after damage to the nigrostriatal pathway has been started experimentally and this works when it is delivered directly into the brain or intravenously. This therapy thus represents an exciting new disease modifying agent for PD.
Objectives for Supplemental Investigation:
In order to assess the true capacity of this novel therapeutic agent to protect against cell loss and to determine how best to maximize its efficacy, we will analyze neuronal protection in a chronic, long-term, pre-clinical model of PD. This model will allow a much longer time-course of disease progression to be studied and during which time we will be able to determine the optimal frequency and time course of delivery of this novel therapeutic.
We also propose to analyze, at the level of the mitochondria, how the interaction between the viral RNA and mitochondrial Complex I results in protection of these neurons.
Importance of This Research for the Development of a New PD Therapy:
We have already shown that a novel viral RNA we have previously identified is able to protect neurons of the substantia nigra in pre-clinical models of PD. However, due to the speed of disease progression in these models, there is an insufficient time window in which to analyze how and when the therapeutic should be delivered to maximize its efficacy. The work proposed will allow us to address these important questions to allow us to move this novel therapeutic more rapidly towards the clinic.
Previously, we identified a viral RNA which could act as a novel protective agent in models of PD when delivered before experimental damage to neurons of the substantia nigra (SN). We observed that this viral RNA was protective when delivered directly to the brain, and when it was delivered by injection into the bloodstream. In both cases, the viral RNA inhibited neuronal cell death.
To help determine if this novel therapeutic could also show efficacy in an alternative pre-clinical model of PD, we have tested whether it protects rats from over-expression of alpha-synuclein.
We have now shown that this novel therapeutic can, indeed, protect animals from symptoms of PD due to the over-expression of alpha-synuclein and that this also occurs by protection from mitochondrial stress.
Professor of Molecular Virology in the Department of Medicine at University of Cambridge
Location: Cambridge, United Kingdom