Gene therapy approaches for obesity-induced adipose neuropathy: Device-targeted AAV-mediated neurotrophic factor delivery to adipocytes in subcutaneous adipose

Abstract

Maintaining functional adipose innervation is critical for metabolic health. We found that subcutaneous white adipose tissue (scWAT) undergoes peripheral neuropathy (PN) with obesity, diabetes, and aging (reduced small fiber innervation, nerve/synaptic/growth-cone/vesicle markers, altered nerve activity). Unlike peripheral nerve injuries, peripheral nerves don’t regenerate with PN, therefore, new therapies are needed for treatment of this condition that affects 20-30 million Americans. Here we validated a gene therapy approach using an adipocyte-tropic adeno-associated virus (AAV; serotype Rec2) to deliver neurotrophic factors (BDNF and nerve growth factor, NGF) directly to scWAT to improve tissue-specific PN as a proof-of-concept approach. AAVRec2-BDNF intra-adipose delivery improved tissue innervation in obese/diabetic mice with PN, but after longer periods of dietary obesity there was reduced AAVRec2-BDNF effectiveness, revealing a key window for therapies. AAVRec2-NGF increased scWAT innervation in obese mice and was more effective than BDNF, likely because Rec2 targeted adipocytes, the tissue's endogenous NGF source. AAVRec2-NGF also worked well even after 25 weeks of dietary obesity, unlike BDNF which likely needs a vector that targets its physiological cellular source in the stromal vascular fraction of the tissue. Given the differing effects of AAVs carrying NGF versus BDNF, a combined therapy may be ideal for obesity/diabetes neuropathy.