Endogenous Reprogramming of Alpha Cells into Beta Cells, Induced by Viral Gene Therapy, Reverses Autoimmune Diabetes

Abstract

Successful strategies for treating type 1 diabetes need to restore the function of pancreatic beta cells that are destroyed by the immune system and overcome further destruction of insulin-producing cells. Here, we infused adeno-associated virus carrying Pdx1 and MafA expression cassettes through the pancreatic duct to reprogram alpha cells into functional beta cells and normalized blood glucose in both beta cell-toxin-induced diabetic mice and in autoimmune non-obese diabetic (NOD) mice. The euglycemia in toxin-induced diabetic mice and new insulin cells persisted in the autoimmune NOD mice for 4 months prior to reestablishment of autoimmune diabetes. This gene therapy strategy also induced alpha to beta cell conversion in toxin-treated human islets, which restored blood glucose levels in NOD/SCID mice upon transplantation. Hence, this strategy could represent a new therapeutic approach, perhaps complemented by immunosuppression, to bolster endogenous insulin production. Our study thus provides a potential basis for further investigation in human type 1 diabetes.

Pancreas regeneration

“…Several studies have suggested that human α-cells in islets can be reprogrammed to become β-cells 42,120 . Changes in α-cell to β-cell ratios and the appearance of cells positive for both glucagon and insulin have provided some evidence for such conversions; however, in the absence of lineage tracing, direct evidence is still lacking.…”

“…Focused studies of these β-cells in human samples and deeper understanding of the heterogeneity of human β-cells may eventually yield molecular targets that allow the production of functional insulin-secreting cells that resist autoimmunity. β-Cells derived from reprogramming of α-cells have been shown to resist autoimmunity in mouse studies, providing another potential path to study and possibly produce autoimmune-resistant β-cells 120 . Finally, it may be possible to genetically modify β-cells so that they are able to avoid detection or elimination by the autoimmune cells.…”

Using a barcoded AAV capsid library to select for novel clinically relevant gene therapy vectors

“…The vectors generated in our study could be used for gene therapy of diabetes by delivering transcription factors or small hairpin RNAs (shRNA) into pancreatic islet cells. The overexpression or inhibition of several transcription factors, such as Pdx1, Ngn3, MafA , Pax4, and Arx was found to effectively convert pancreatic islet progenitors and committed islet α-cells into β-cells (Chakravarthy et al, 2017;Collombat et al, 2009;Furuyama et al, 2019;Matsuoka et al, 2017;Wang et al, 2018;Xiao et al, 2018;Zhang et al, 2016). Moreover, expression of other factors, such as Igf1 and Follistatin has also shown promise in preserving β-cell mass or protecting newly transplanted donor islets from apoptosis (Mallol et al, 2017;Zhao et al, 2015).…”

“…Over a period of 30 weeks, this gene therapy strategy was successfull in counteracting progression to autoimmune diabetes. Another strategy for the treatment of diabetes is the conversion of glucagon producing α-cells or other endocrine or exocrine pancreatic cell types into β-cells by overexpression or repression of certain transcription factors, such as Pdx1, Ngn3, MafA , Pax4, and Arx (Chakravarthy et al, 2017;Collombat et al, 2009;Courtney et al, 2013;Furuyama et al, 2019;Lima et al, 2016;Matsuoka et al, 2017;Wang et al, 2018;Xiao et al, 2018;Zhang et al, 2016) (for a review see (Vieira et al, 2016)). For the studies that utilized rAAV for gene delivery into murine islet cells, AAV8 had been used as this serotype was shown to be efficient for transduction.…”

Are we aiming to miss in translational autoimmunity treatments?

“…In such mouse models, many potential therapeutics demonstrate great effects in preventing the development of disease, ameliorating the disease symptoms, or even curing the fulminant autoimmunity 1– 5 . However, when applying therapeutics in translational medicine, clinical trials often are disappointing, demonstrating low or short-lived efficacy 6– 8 .…”