Genome Editing Human Pluripotent Stem Cells to Model β-Cell Disease and Unmask Novel Genetic Modifiers

Abstract

A mechanistic understanding of the genetic basis of complex diseases such as diabetes mellitus remain elusive due in large part to the activity of genetic disease modifiers that impact the penetrance and/or presentation of disease phenotypes. In the face of such complexity, rare forms of diabetes that result from single-gene mutations (monogenic diabetes) can be used to model the contribution of individual genetic factors to pancreatic β-cell dysfunction and the breakdown of glucose homeostasis. Here we review the contribution of protein coding and non-protein coding genetic disease modifiers to the pathogenesis of diabetes subtypes, as well as how recent technological advances in the generation, differentiation, and genome editing of human pluripotent stem cells (hPSC) enable the development of cell-based disease models. Finally, we describe a disease modifier discovery platform that utilizes these technologies to identify novel genetic modifiers using induced pluripotent stem cells (iPSC) derived from patients with monogenic diabetes caused by heterozygous mutations.

Stem cell-based multi-tissue platforms to model human autoimmune diabetes

“…Genome engineering has been used to model monogenic diabetes by knocking out genes critical for pancreatic and β cell development in hPSCs (PDX1, NEUROG3, ARX, GLIS3, NEUROD1) (reviewed in [ 57 , 58 ]). Correcting mutations in patient-derived iPSCs has led to a better understanding of disease mechanisms in rare cases of neonatal diabetes [ [59] , [60] , [61] ].…”