GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models

Abstract

Aims/hypothesis Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. Methods The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. Results Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons. Conclusions/interpretation Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome. Graphical abstract

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

“…However, it is also associated with a number of neurological complications and psychiatric manifestations. Several studies have proven ER stress-mediated death of beta cells in WS, and therapeutic potential for diabetes medications such as glucagon-like peptide 1 receptor agonists [17, 44, 45]. In contrast, the disease mechanisms underlying the neurological and psychiatric manifestations of WS are less well understood, and recently oligodendrocytes have gotten increased attention.…”

“…Notably, until today, research has mainly focused on the diabetic phenotype of WS and the aforementioned WFS1 functions have mostly been studied in the islets of Langerhans and ý-cells of the pancreas [17, 26]. However, diabetes has become a chronic illness that can be managed via drug therapy and only has a limited impact on the quality of life of Wolfram patients.…”

Cardiac Wolframinopathies: A Case Report of Myocarditis and a Literature Review of Cardiac Involvement in Wolfram Syndrome 1

“…The main mechanism seems to be the modulation of the dysregulated ER stress signaling that occurs in WS1 [ 3 ]. Other studies have demonstrated that exenatide and dulaglutide improved β-cell function by improving mitochondrial function, reducing oxidative stress, and preventing apoptosis in preclinical models of WS1 [ 37 ].…”

LncRNA ARGI Contributes to Virus‐Induced Pancreatic β Cell Inflammation Through Transcriptional Activation of IFN‐Stimulated Genes

“…[ 62 , 63 ] The use of iPSC‐derived human islet‐like aggregates constitutes a useful and disease‐relevant alternative to human islets to perform in vitro studies in diabetes. [ 64 , 65 , 66 ] However, some genetic manipulations are particularly inefficient in these cells such as plasmid‐mediated protein overexpression and gene silencing of very low expressed gene targets, as is the case for lncRNAs. [ 63 , 67 ] In the context of this manuscript, the technical issues associated with the genetic manipulation of iPSC‐derived human islet‐like aggregates impeded the validation of some results obtained in EndoC‐ β H1cells, pointing to the future need to fine tune these in vitro approaches and to develop novel techniques to efficiently modify the expression of low abundance non‐coding transcripts.…”