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

Autor:	Blaszkiewicz M; Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA., Tao T; Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA., Mensah-Arhin K; Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA., Willows JW; Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA., Bates R; Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, USA., Huang W; Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, USA., Cao L; Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210, USA., Smith RL; College of Engineering, University of Maine, Orono, ME 04469, USA., Townsend KL; Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA; College of Engineering, University of Maine, Orono, ME 04469, USA. Electronic address: kristy.townsend@osumc.edu.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 May 01; Vol. 32 (5), pp. 1407-1424. Date of Electronic Publication: 2024 Mar 01.
DOI:	10.1016/j.ymthe.2024.02.035
Abstrakt:	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 and nerve/synaptic/growth-cone/vesicle markers, altered nerve activity). Unlike with nerve injuries, peripheral nerves do not regenerate with PN, and therefore new therapies are needed for treatment of this condition affecting 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 (brain-derived neurotrophic factor [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 efficacy, revealing a key time window for therapies. AAVRec2-NGF also 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 (stromal vascular fraction cells). Given the differing effects of AAVs carrying NGF versus BDNF, a combined therapy may be ideal for PN. Competing Interests: Declaration of interests K.L.T. and M.B. are co-founders of Neuright, Inc., a University of Maine spin-out and biotechnology R&D start-up company based in Maine and Ohio, which provided DEN-TEN devices for this study. Neuright, Inc., holds a licensing agreement with UMaine to continue R&D and commercialization for this device, and will conduct future human testing studies. K.T.L., M.B., and R.L.S. are also named as inventors on a patent filed by UMaine pertaining to the device described in this manuscript. Patent Application Number 17/923,293. Status: Application Undergoing Preexam Processing 11/04/2022. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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