Osteopontin Gene Therapy as a Neuroprotective Treatment for Parkinson's Disease

Objective/Rationale:

Current approaches aimed at slowing or stopping the progression of Parkinson’s disease (PD) have failed due to primarily focusing on targeting specific points on the cell death pathway. By targeting endogenous proteins that are involved in multiple processes that contribute to disease pathogenesis may provide a more successful approach to neuroprotection. One such protein, osteopontin (OPN) is present in human nigral dopaminergic neurones and its expression is decreased in PD. Furthermore, we have shown that an OPN fragment neuroprotects dopaminergic neurones both in vitro and in vivo whilst OPN inactivation results in cell death.

Project Description:

We will investigate the feasibility of delivering OPN to the brain through a gene therapy approach that utilises viral vectors. Adeno-associated vectors (AAV) encoding rat or human OPN gene will be investigated first in vitro in primary rat ventral mesencephalic and striatal neurones and their neuroprotective effects will be determined against toxin induced cell death. Following this we will determine the expression and spread of OPN expression in the rat prior to assessing the neuroprotective effects of the AAV-OPN in the 6-hydroxydopamine pre-clinical model of PD. Behavioural and biochemical techniques will be used to assess the efficacy of this approach as a treatment for PD.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:

By focussing on the replacement of a natural endogenous neuroprotectant protein that is deficient in PD and is able to target several points on the cell death pathway may be a more efficient means of slowing or stopping disease progression. By utilising a gene therapy approach to deliver the protein will overcome the issue of how to target specific brain regions and will ensure that OPN exerts its effects in the regions most affected by PD.

Anticipated Outcome:

This study will provide further information on the role that OPN has to play in the pathogenesis of PD. Furthermore, this strategy may result in a single procedure that has long lasting effects on PD progression and as it is not reliant on the use of agents that exert effects not normally present in the brain may ultimately provide a clinical therapy that will slow or halt disease progression in patients.