Pre-clinical therapy delivery and imaging of nerve recovery in diabetic peripheral neuropathy of adipose and skin.
Diabetic peripheral neuropathy (DPN) is a debilitating condition that affects more than 50% of diabetic patients, and likely also impacts pre-diabetic patients. There is currently no treatment for diabetic neuropathy, aside from pain management, and pain is just one of numerous complex neurological symptoms. We have recently discovered that diabetic neuropathy in mouse and human extends beneath the skin to the underlying subcutaneous white adipose tissue (scWAT), where loss of proper nerve supply impacts metabolic health and brain-adipose neural communication for the regulation of energy expenditure. We have further identified that brain derived neurotrophic factor (BDNF) is secreted in scWAT after cold stimulation, a process that promotes neurite outgrowth, that the BDNF is released from specialized neuroimmune cells that home to the tissue, and that deletion of BDNF from these myeloid lineage neuroimmune cells leads to denervation of scWAT and loss of metabolic control. We have piloted the use of AAV-BDNF intra-adipose injections as a potential therapy for diabetic neuropathy, and find promising results. The current project builds on these findings to utilize a microneedle array we have developed to allow precise delivery of AAV-BDNF therapy to skin and adipose, followed by our own technique for 3D imaging of tissue innervation to monitor nerve regrowth. This pre-clinical approach will be optimized under this award, so that we can move this therapy into human populations.

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