Neurogenic tissue nanotransfection in the management of cutaneous diabetic polyneuropathy

This work rests on our recent report on the successful use of tissue nanotransfection (TNT) delivery of Ascl1, Brn2, and Myt1l (TNTABM) to directly convert skin fibroblasts into electrophysiologically active induced neuronal cells (iN) in vivo. Here we report that in addition to successful neurogenic conversion of cells, TNTABM caused neurotrophic enrichment of the skin stroma. Thus, we asked whether such neurotrophic milieu of the skin can be leveraged to rescue pre-existing nerve fibers under chronic diabetic conditions. Topical cutaneous TNTABM caused elevation of endogenous NGF and other co-regulated neurotrophic factors such as Nt3. TNTABM spared loss of cutaneous PGP9.5+ mature nerve fibers in db/db diabetic mice. This is the first study demonstrating that under conditions of in vivo reprogramming, changes in the tissue microenvironment can be leveraged for therapeutic purposes such as the rescue of pre-existing nerve fibers from its predictable path of loss under conditions of diabetes. Tissue nanotransfection (TNT) based non-viral delivery of neurogenic reprograming factors to skin in vivo converted skin fibroblasts into induced neuronal cells (iN). At the same time stroma of the reprogramed skin site is enriched in neurotrophic factors to support iN survival and maturation. This neurotrophic enrichment of the skin stroma was leveraged to preserve pre-existing cutaneous nerve fibers in the diabetic skin which is otherwise known to undergo a degenerative fate. This constitutes first evidence that the reprogramed tissue microenvironment, independent of the induced cell itself, can be of direct therapeutic value. [Display omitted]