First-ever gene therapy approach for peripheral neuropathy in obese/diabetic mice

COLUMBUS, Ohio – A first-ever study of a new gene therapy approach could one day help people who suffer from painful nerve damage, known as peripheral neuropathy, that has no known cure.

The top cause of neuropathy is diabetes, which can impact more than half of patients with this disease.

 

Researchers at The Ohio State University Wexner Medical Center and College of Medicine https://medicine.osu.edu/led the gene therapy mouse study that is published online in the journal Molecular Therapy.

 

The team used a therapeutic viral construct (adeno-associated virus or AAV) to deliver proteins called neurotrophic factors to the fatty (adipose) tissue under the skin. The job of these proteins is to help nerve cells survive, grow, and regenerate. 

 

“Treating neuropathy in multiple tissues and organs affected by disease, including adipose tissue, is critical. Prior attempts to use neurotrophic factors were unsuccessful,” said Kristy Townsend, PhD, associate professor in the Department of Neurosurgery at Ohio State. “We have overcome this hurdle by using AAV-based gene therapy to overexpress two critical neurotrophic factors for nerve survival, plasticity, and regeneration: nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). This allows longer-term expression of these proteins, and can target expression to certain cell types, thereby avoiding unwanted side effects.”

 

The team provided the gene therapy two ways. Both methods – a standard syringe and a new theragnostic device platform (combining therapy and diagnostic functions) delivered AAV-containing fluids and improved tissue-specific peripheral neuropathy, but the device was able to target the treatment to a specific tissue layer. 

 

“Our technical advances and approach innovations, as well as the clinical translational relevance of these gene therapy findings, could lead to new therapies,” Townsend said.

 

The theragnostic platform is called the Detecting Early Neuropathy to Treat Early Neuropathy (DEN-TEN). It is a microneedle array used for subdermal tissue delivery of AAV-mediated gene therapy.

 

Townsend is co-founder, Chief Scientific Officer and Chair of the Board for Neuright, Inc., which developed the DEN-TEN, which is patent pending. Other researchers on the project were from the Department of Cancer Biology and Genetics at Ohio State and the College of Engineering at the University of Maine. 

 

Townsend studies how the nervous system is affected with metabolic diseases, such as obesity, diabetes, aging, cardiometabolic disease and peripheral neuropathy. Her previous work, which has been validated by other groups, demonstrated significant neuropathy extending under the skin to the fat tissues. 

 

“This finding is relevant given the critical role that brain-adipose neural communication plays in metabolic physiology. Loss of the nerve supply in fat tissue negatively impacts metabolic regulation, and thus ‘adipose neuropathy’ can worsen these metabolic disease states,” said Townsend, who is also a member of Ohio State’s Gene Therapy Institute and Diabetes and Metabolism Research Center.. 

 

With peripheral neuropathy, multiple nerve types can degenerate. Symptoms are therefore complex, and can include numbness, tingling, burning, pain and motor loss. In severe cases, patients may need to have a limb amputated. This proof of concept study paves the way for future gene therapies that may target other cells and tissues, to provide support for nerve regeneration.

 

“The timing of the therapies early in the course of developing diabetic peripheral neuropathy also is a crucial factor. There is likely a ‘critical window’ when treatments can be most effective,” said Townsend. “A combination gene therapy approach targeting neurotrophic factors to their endogenous cell source and delivered early in the course of disease is likely to be the most effective treatment.”

 

The Townsend Lab was funded by a NIDDK Diabetic Complications Consortium grant, and start-up funding from University of Maine and The Ohio State University. Neuright, Inc. was funded by grants from the Maine Technology Institute, and a Phase 1 STTR from the National Science Foundation.

 

Authors declare no competing non-financial interests, but the following competing financial interests remain: Kristy L. Townsend and Magdalena Blaszkiewicz are co-founders of Neuright, Inc., a University of Maine spinout and biotechnology R&D start-up company based in Maine and Ohio, which provided DEN-TEN devices for this study. 

 

Neuright, Inc. holds an exclusive license agreement with UMaine to continue R&D and commercialization for the DEN-TEN device and will conduct future human testing studies. Townsend, Blaszkiewicz and Rosemary L. Smith are also named as inventors on a patent filed by UMaine pertaining to the device described in this study.

 

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