From Pancreatic β-Cell Gene Networks to Novel Therapies for Type 1 Diabetes

Abstract

Completion of the Human Genome Project enabled a novel systems- and network-level understanding of biology, but this remains to be applied for understanding the pathogenesis of type 1 diabetes (T1D). We propose that defining the key gene regulatory networks that drive β-cell dysfunction and death in T1D might enable the design of therapies that target the core disease mechanism, namely, the progressive loss of pancreatic β-cells. Indeed, many successful drugs do not directly target individual disease genes but, rather, modulate the consequences of defective steps, targeting proteins located one or two steps downstream. If we transpose this to the T1D situation, it makes sense to target the pathways that modulate the β-cell responses to the immune assault—in relation to signals that may stimulate the immune response (e.g., HLA class I and chemokine overexpression and/or neoantigen expression) or inhibit the invading immune cells (e.g., PDL1 and HLA-E expression)—instead of targeting only the immune system, as it is usually proposed. Here we discuss the importance of a focus on β-cells in T1D, lessons learned from other autoimmune diseases, the “alternative splicing connection,” data mining, and drug repurposing to protect β-cells in T1D and then some of the initial candidates under testing for β-cell protection.

Transcription and splicing regulation by NLRC5 shape the interferon response in human pancreatic β cells

“…Recent evidence suggests that stress pathways triggered within β cells initiate and/or accelerate autoimmune β cell destruction ( 3 , 5 ). Multiple layers of evidence implicate interferon α (IFNα) signaling as a key component of the early stages of T1D pathophysiology ( 6 ). Type I IFN is expressed in pancreatic islets from people with T1D, and islets obtained from living donors with recent-onset T1D show an IFN-stimulated gene signature ( 3 , 7 ).…”

Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction

“…The use of isogenic hESC platforms and patient-derived iPSCs to survey the genetics of T1D at multiple cellular levels has been suggested in the literature [ 250 , 251 , 252 ]. Studies with patient-derived stem cells to model T1D include examples such as: the use of iPSC-derived SC-β to evaluate their response to cytokines [ 253 , 254 ], generation of iPSC-derived APCs to model their interaction with T cells [ 255 ] or complex autologous platforms with iPSC-derived SC-β and immune cells from the same patients [ 256 ].…”

“…Others have also probed the response of iPSC-derived SC-β to cytokines [ 253 , 254 ] or study their interaction with immune cells in complex isogenic systems [ 257 ]. The use of gene-editing techniques on iPSC/hESC to study T1D-predisposing SNPs in response to cytokines or interaction with immune cells is an approach that has already been considered [ 251 ]. Several other studies have focused on the influence of genetic variants on β cell ER stress.…”

The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α

“…Several studies reported the prominent role of IFNα in the induction of autoimmunity in T1D (23). Since TYK2 is important for the IFN-I signaling mediated through IFNAR1, we took advantage of our TYK2 KO model to understand its role during the dialogue between IFNα and the developing pancreatic islet cells.…”