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. 2024 Jul;16(7):1490-1494.
doi: 10.1038/s44321-024-00089-z. Epub 2024 Jun 6.

Gene therapy targeting key beta cell regulators as a potential intervention for diabetes

Wing Yan So  1 , Weiping Han  2
Affiliations

Gene therapy targeting key beta cell regulators as a potential intervention for diabetes

Wing Yan So et al. EMBO Mol Med. 2024 Jul.

Abstract

Loss of functional beta cells is the central event of all forms of diabetes. Conventional therapies for type 2 diabetes (T2D) fail to preserve beta cells, leading to worsening glycemia as beta cell function progressively declines. While immunotherapies for type 1 diabetes (T1D) have been unsuccessful, emerging evidence suggests that therapies to revitalize beta cells are essential to reverse T1D. Islet transplantation represents a promising beta cell replacement therapy. However, its widespread application is limited by the scarcity of available islets and post-transplant islet graft loss. Hence, preserving beta cells is fundamental for managing all types of diabetes. Several key beta cell regulators, including pancreatic and duodenal homeobox 1 (PDX1), v-Maf musculoaponeurotic fibrosarcoma oncogene family protein A (MAFA), and paired box 6 (PAX6), are crucial for beta cell function, with their dysregulation tightly linked to beta cell dysfunction. In this commentary, we summarize the roles of PDX1, MAFA, and PAX6 in determining beta cell function and diabetes development. We also explore the potential of gene therapy that delivers these beta cell regulators as therapeutic interventions to rescue beta cell function in diabetes and discuss the strategies of combining gene therapy with cell therapy to enhance islet transplant efficacy.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1. Schematic overview of the gene therapies delivering PDX1, MAFA, or PAX6 to reverse diabetes.
(A) In vivo administration of adenovirus or AAV carrying PDX1 and MAFA expression cassette reprograms acinar cells or alpha cells into insulin-producing cells and alleviates hyperglycemia in both induced and autoimmune diabetic mice. In vivo delivery of AAV carrying Pax6 gene stimulates beta cell proliferation and ameliorates glycemic perturbation in STZ-induced diabetic mice. (B) Transgenic overexpression of PDX1 or MAFA in beta cells of T2D mice (IRS2-deficient mice or db/db mice), and in vivo AAV-mediated Pax6 gene delivery in db/db mouse beta cells increase beta cell mass and improve glucose homeostasis.
Figure 2
Figure 2. Schematic overview of combining gene therapy targeting PDX1, MAFA, and PAX6 with cell therapy to enhance islet transplant efficacy for diabetes management.
Ex vivo treatment of human islets with AAV-PAX6 enhances islet graft function and improves islet transplant efficacy. Human alpha cells can be reprogrammed into beta-like cells after transduction with AAV carrying PDX1 and MAFA genes. Pancreatic exocrine and ductal cells can be reprogrammed into insulin-producing cells through adenovirus-mediated delivery of expression cassette containing PDX1/MAFA or PDX1/MAFA/PAX6. The induced insulin-producing cells display hallmark features of functional beta cells and provide sustained normalization of glycemia after transplantation into diabetic immunodeficient mice.
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