Paired box 6 gene delivery preserves beta cells and improves islet transplantation efficacy

Abstract

Loss of pancreatic beta cells is the central feature of all forms of diabetes. Current therapies fail to halt the declined beta cell mass. Thus, strategies to preserve beta cells are imperatively needed. In this study, we identified paired box 6 (PAX6) as a critical regulator of beta cell survival. Under diabetic conditions, the human beta cell line EndoC‐βH1, db/db mouse and human islets displayed dampened insulin and incretin signalings and reduced beta cell survival, which were alleviated by PAX6 overexpression. Adeno‐associated virus (AAV)‐mediated PAX6 overexpression in beta cells of streptozotocin‐induced diabetic mice and db/db mice led to a sustained maintenance of glucose homeostasis. AAV‐PAX6 transduction in human islets reduced islet graft loss and improved glycemic control after transplantation into immunodeficient diabetic mice. Our study highlights a previously unappreciated role for PAX6 in beta cell survival and raises the possibility that ex vivo PAX6 gene transfer into islets prior to transplantation might enhance islet graft function and transplantation outcome.

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

“…Besides, db/db mice with beta cell-specific overexpression of the Mafa gene display increased beta cell mass through suppression of beta cell apoptosis, elevated plasma insulin level, and improved glycemia (Matsuoka et al, 2015 ). Moreover, adeno-associated virus (AAV)-mediated Pax6 gene delivery in db/db mouse beta cells enhances GSIS, beta cell survival, and maintains beta cell identity, which in turn alleviates glycemic perturbation (So et al, 2023 ; So et al, 2021 ). These findings demonstrate that gene therapy delivering Pdx1 , Mafa , or Pax6 genes into beta cells of T2D mice could effectively preserve the residual beta cells and potentiate their function, thereby reversing diabetes (Fig.…”

“…Augmented proliferation of residual beta cells is the predominant mechanism to reconstitute a functional beta cell mass in response to partial beta cell ablation. In this respect, AAV-mediated Pax6 gene delivery into beta cells of streptozotocin (STZ)-induced diabetic mice stimulates beta cell proliferation and inhibits beta cell apoptosis, which increases beta cell mass and ameliorates glycemic perturbation (So et al, 2023 ).…”

“…In humans, a null mutation in the PDX1 gene has been identified to cause pancreatic agenesis when homozygous and maturity-onset diabetes mellitus of the young when heterozygous (Zhang et al, 2022 ). In addition, inactivation of the PDX1 gene has been observed in islets of individuals with T2D, suggesting that dysregulation of PDX1 is implicated in beta cell dysfunction in human diabetes (So et al, 2023 ).…”

“…Single-cell RNA-Seq data reveal that subpopulations of human islet cells co-expressing MAFA and MAFB represent highly functional and mature beta cell subpopulations (Nishimura et al, 2022 ). Islets of T2D patients display a marked reduction in MAFA expression (So et al, 2023 ), which leads to beta cells losing their mature phenotype and undergoing dedifferentiation.…”

“…Notably, recent studies have revealed that PAX6 regulates GSIS, beta cell survival, and identity in human beta cells. Down-regulation of PAX6 expression is implicated in beta cell dysfunction in diabetes (So et al, 2023 ; So et al, 2021 ). These observations underscore the essential regulatory role of PAX6 in human beta cell function, with its dysfunction tightly linked to diabetes pathogenesis.…”