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Novel Method for Therapeutic Gene Silencing in the Brain

Reducing the activity of certain genes — called gene silencing — implicated in Parkinson’s disease may be a therapeutic approach that could prevent or slow the disease. These researchers will study a new method for gene silencing to understand how this treatment can be distributed in the brain to suppress the expression of alpha-synuclein in brain neurons of pre-clinical models.

Project Description:             
Molecules will be designed and then tested in tissue culture to identify a lead molecule with highest therapeutic potential. Subsequently, the best molecule will be administered using different doses and routes of application. The time course and movement of these molecules in brain will be studied using microscopy. The effect of the treatment with a carrier molecule designed to improve the distribution to desired regions of the brain will also be studied.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
If successful, this therapeutic approach will open up a new form of treatment for patients with Parkinson’s disease. Additionally, if one gene can be suppressed, others may be able to be silenced, too. The choice of which gene and which region to target could be decided for each patient depending on their unique circumstances.

Anticipated Outcome:          
Researchers hope to identify a specific molecule that will suppress the expression of alpha-synuclein, which has been implicated in both familial and sporadic Parkinson’s disease. They also hope to achieve two other important outcomes: 1) identify the best way to administer this molecule to achieve wide-spread and long-term distribution of the molecule and 2) identify that this molecule is present in neurons of the brain.

Final Outcome

Switching off certain disease-linked genes -- an approach called gene silencing -- may prevent or slow the disease. Using a new gene silencing technology called U1 Adaptor, we found that two different molecules [U1 Adaptor Oligonucleotides (U1AOs)] have gene-silencing potential in pre-clinical models. When injected into pre-clinical models, both U1AO molecules gathered inside brain cells, staying there for at least five days after the injection. Both U1AOs retained their therapeutic activity while they traveled from the site of injection to the brain. Specifically, they disrupted the production of alpha-synuclein, a sticky protein that clumps in the brains of people with Parkinson's disease (PD). Compared with other gene silencing technologies, the low dose of U1AO needed to achieve these results mitigates the risk of unwanted side effects. These results are encouraging because, for the first time, the suppression of a single Parkinson's-linked gene was accomplished in pre-clinical models, demonstrating a potential of U1AOs to treat Parkinson's disease.

November 2014


  • Eric K. Richfield, MD, PhD

    Piscataway, NJ United States

  • Samuel I. Gunderson, PhD

    Piscataway, NJ United States

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