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Funded Studies

Gene delivery of miRNAs to reduce alpha synuclein: a new therapy for PD

Objective/Rationale: 
Alpha synuclein is a protein that in excessive amounts is implicated in Parkinson’s disease (PD). Alpha synuclein is also known to be the major constituent of a signature patholological feature of PD called a Lewy body, This grant plans to reduce the levels of experimental Parkinson’s disease using a gene therapy approach to deliver microRNAs in which the synthesis of alpha synuclein is inhibited. Two specific microRNAs will be tested for both behavioral and anatomical neuroprotection.
Project Description: 
Pre-clinical models will be treated with a neurotoxin called MPTP. This neurotoxin causes dopamine cell death in part by accumulating alpha-synuclein. Prior to the MPTP lesion, they will receive an injection into the substantia nigra of a lentivirus encoding for microRNAs 7 and 153. These two microRNAs have been shown to reduce alpha-synuclein levels in culture. We will use a battery of tests including the stepping test and cylinder test to assess whether the lenti-microRNA’s can functionally reduce motor disabilities induced by this toxin. Then the models will be sacrificed and the abilities of these microRNA’s to reduce the MPTP-induced degenerative process in the nigrostriatal system will be assessed.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
It is now  appreciated that alpha synuclein over expression and misfolding is a major pathological feature in Parkinson’s disease. Methods that reduce alpha synuclein expression could lead to a major treatment paradigm shift in the treatment of Parkinson’s disease. This grant will test the hypothesis that gene delivery of microRNA’s the non-coding region of protein RNA synthesis, can reduce the structural and functional expression of alpha synuclein in the nigrostriatal system. If successful, this can be applied to other regions in which alpha synuclein accumulates.
Anticipated Outcome: 
We expect to learn the following:

  • Can we successfully deliver microRNA’s using gene therapy
  • Can gene delivery of microRNA’s 7 and 153 reduce motor disability in MPTP-treated pre-clinical models
  • Can gene delivery of microRNA’s 7 and 153 protect the nigrostriatal system from MPTP toxicity.
     

Researchers

  • Jeffrey H. Kordower, PhD

    Chicago, IL United States


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