21-LB: Transdermal Microneedle Device Delivery of Adipocyte-Specific AAVs to Overexpress Adipose Tissue Neurotrophic Factors in the Treatment of Diabetic Peripheral Neuropathy

Abstract

Diabetes is the leading cause of peripheral neuropathy (PN) , which results in loss of nerve supply in tissues like skin, adipose and muscle. While there are currently few treatments for PN, early mitigation in the pre-diabetic state with tissue neurotrophic factors may improve nerve function in metabolically important tissues like adipose. We used an adipocyte-tropic adeno-associated virus (AAV; serotype Rec2) to deliver neurotrophic factors directly to scWAT using a transdermal microneedle device that we developed. This approach avoids potential off-target effects and aberrant axon outgrowth in skin that may increase pain. Using both the BTBRob/ob and C57BL/6J diet-induced neuropathy mouse models, we have demonstrated that AAVRec2-BDNF (brain derived neurotrophic factor, which we have implicated in controlling adipose innervation) delivery to scWAT with our device increased tissue innervation 14 days after treatment, marked by increased protein expression of pan-neuronal marker PGP9.5 and sympathetic nerve marker tyrosine hydroxylase (TH) . Longer periods of dietary obesity (25+ wks vs 16 wks) blunted the ability of AAVRec2-BDNF to increase innervation in scWAT, despite these mice showing an initial decrease in body weight compared to controls. This indicates there may be a critical window for therapy delivery during the progression to diabetic neuropathy during which interventions are more advantageous. Treatment with AAVRec2-NGF (nerve growth factor) also increased scWAT innervation in obese mice at 8 weeks post-treatment, as evidenced by increased protein expression of PGP9.5, TH and markers of axon outgrowth (Gap43, Vasp) . Thermal imaging above inguinal scWAT revealed an increase in temperature only in AAVRec2-NGF treated mice, supporting the idea that NGF-responsive nerves drive tissue browning and/or thermogenesis. Taken together, we have developed a novel treatment approach for delivering adipocyte-tropic AAVs to overexpress neurotrophic factors as a means to mitigate diabetes-associated PN. Disclosure M. Blaszkiewicz: None. K. L. Townsend: Other Relationship; Neuright, Inc.