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GLP-1 receptor agonists show promise for Wolfram syndrome

22nd June 2023

Preclinical findings reported in a recent issue of Diabetologia suggest that GLP-1 receptor agonists can improve beta cell and neuronal functioning in Wolfram syndrome, promising a new approach to this rare disease. Dr Susan Aldridge reports. 

Wolfram syndrome is a rare autosomal recessive disorder that affects around one in 700,000 people. It is caused by mutations in the Wfs1 gene, which codes for the endoplasmic reticulum (ER) transmembrane protein WFS1, also known as wolframin. Those affected develop insulin-dependent diabetes, optic nerve atrophy, diabetes insipidus and hearing loss. They may also have cerebellar ataxia, gait and balance issues, memory loss and psychiatric problems. There are currently no licensed treatments to prevent or delay the condition. 

The pathophysiology of Wolfram syndrome involves the ER, an essential organelle in both pancreatic beta cells and neurons. Deficiency in WFS1 causes ER stress, which can lead to cell dysfunction and death if prolonged. In beta cells, WFS1 deficiency impairs insulin synthesis and secretion, and induces apoptosis. In the brain, it results in delayed neuronal development and impaired neuronal survival. 

Glucagon-like peptide-1 is an incretin hormone which, on binding to its receptor (GLP-1R), enhances insulin secretion and beta cell survival, including in conditions of ER stress. Exploiting these properties, GLP-1 receptor agonists are used increasingly to treat type 2 diabetes. GLP-1 receptor agonists are expressed in many cells, including neurons, and they can cross the blood-brain barrier and provide neuroprotection. They have therefore been investigated as a potential therapy for neurodegeneration and vision loss in Wolfram syndrome, as well as for the diabetes that occurs with the condition. 

Findings from experiments in WFS1-deficient mice have been promising, but it can be hard to predict the translation of such findings to human disease. Therefore, Mariana Igoillo-Esteve of the Université Libre de Bruxelles Center for Diabetes Research in Brussels and colleagues elsewhere, set out to test the therapeutic potential of GLP-1 receptor agonists not only in WFS1-deficient mice, but also in human WFS1-deficient beta cells and neurons, and in a humanised mouse model of Wolfram syndrome.

Dulaglutide in WFS-1 deficient mice

Four-week-old Wfs1 knockout and wild-type mice underwent the broad equivalent of a clinical trial in which dulaglutide, a GLP-1 receptor agonist with a half-life of 120 hours, or saline, was administered for eight weeks, followed by a 10-day washout, then treatment was resumed for another four weeks. 

Metabolic tests were done at baseline, during and at the end of the trial. As expected, saline-treated Wfs1 knockout mice developed impaired glucose tolerance when compared with wild-type mice, while dulaglutide normalised glucose tolerance. During the washout, the Wfs1 knockout mice became glucose intolerant again, but this was reversed when the dulaglutide was started again, suggesting that treatment had a transient effect. 

Immunostaining of pancreatic tissue at the end of the experiment showed that islets from the Wfs1 knockout mice had reduced beta cells and enhanced alpha cells compared with wild type mice, so dulaglutide was not able to preserve beta cell mass. 

Further experiments were carried out with seven and 20-week-old Wfs1 knockout mice, which showed that four weeks of dulaglutide treatment normalised glucose tolerance in animals of both ages and this effect was maintained over 12 weeks of treatment. 

Taken together, these findings suggest that dulaglutide has a beneficial effect on glucose tolerance in Wfs1 knockout mice in both preventative and curative settings. However, the GLP-1 receptor agonist was not disease-modifying, as indicated by the loss of glucose tolerance during washout and the absence of effect on beta cell mass. 

Wolfram disease preclinical models

The next step in this research was to genetically manipulate a human beta cell line for reduced expression of Wfs1, which was shown to increase ER stress. Under these conditions, both exenatide and dulaglutide reduced cell death, suggesting they confer some protection against ER stress. 

The researchers then turned to an even more disease-relevant cell line – namely, induced pluripotent stem cell (iPSC)-derived beta cells and cerebellar neurons from people with Wolfram syndrome. These were differentiated into islet-like aggregates and time-course studies showed that exenatide protected the cells from cell death induced by tunicamycin, a known ER stress inducer. Exenatide also improved mitochondrial function in the iPSC-derived neurons. 

Next, these iPSC-derived beta cell aggregates and control aggregates were transplanted into immunodeficient mice. The Wolfram-derived cells secreted less C-peptide than controls, consistent with beta-cell dysfunction and supporting the validity of this model. Fourteen weeks after the transplant, the mice were randomised to dulaglutide or saline. After 12 weeks of treatment, human C-peptide secretion was enhanced in the mice transplanted with Wolfram iPSC-derived beta cells. 

Finally, to assess whether the protective effect of GLP-1 receptor agonists extend beyond beta cells, the researchers generated iPSC-derived neural precursor cells and cerebellar neurons using the cell lines from the individuals with Wolfram syndrome. Exenatide improved mitochondrial function, reduced apoptosis and protected these cells from apoptosis. This suggests that GLP-1 receptor agonists have the therapeutic potential to prevent cerebellar neurodegeneration in Wolfram syndrome.

Looking forward

Wolfram syndrome is a life-threatening disorder that currently has no preventative, therapeutic or curative options, although various drug repurposing studies are underway. In earlier studies, exenatide and liraglutide were shown to prevent and reverse diabetes, enhance insulin secretion and reduce neuroinflammation and vision loss in rodent models of Wolfram syndrome. 

This new study confirms that the long-acting GLP-1 receptor agonist, dulaglutide, also prevents and reverses glucose intolerance and diabetes in Wfs1 knockout mice by enhancing beta cell function. More significantly, GLP-1 receptor agonists also confer protection in different human models of Wolfram syndrome – both in vitro in clonal and primary human beta cells, Wolfram iPSC-derived beta cells, neural precursor cells and cerebellar neurons, and in vivo in humanised mice grafted with Wolfram iPSC-derived beta cells. The findings suggest that GLP-1 receptor agonists may be able to prevent or delay neurodegeneration. They have also shown beneficial effects in other neurodegenerative diseases, such as Friedreich’s ataxia, Parkinson’s disease and Alzheimer’s disease. 

In vivo, an improvement in beta cell function was clear in Wfs1 knockout mice at different ages. Importantly, dulaglutide improved the function of iPSC-derived beta cells in the humanised mouse model of Wolfram syndrome. Recent studies show that liraglutide also provides extra-pancreatic protection in Wfs1 knockout rats, reducing neuroinflammation, improving learning capacity and preventing optic nerve degeneration. 

GLP-1 receptor agonists need to reach all affected tissues to realise their full potential in Wolfram syndrome. Dulaglutide is a large molecule, which might hinder blood-brain barrier crossing. Facilitating this is under investigation for other neurodegenerative diseases and Wolfram syndrome can now be added to that list. 

There is some clinical data on GLP-1 receptor agonist use in people who have Wolfram syndrome. For example, a 16-week administration of liraglutide in an adult with Wolfram syndrome improved glucose tolerance and, in another individual, insulin therapy could be discontinued after treatment with a GLP-1 analogue. Meanwhile, four children with Wolfram syndrome received a seven-to 27-week administration of liraglutide with an increase in C-peptide, at least during the first seven weeks, but it declined thereafter in two who were studied for a longer period. 

This data is promising but controlled trials are needed to assess the safety and efficacy of this approach. This could be an n=1 crossover trial, which is appropriate for such a rare disease. Meanwhile, data extraction from electronic records of individuals with Wolfram syndrome who have, and have not, received GLP-1 receptor agonists will also provide some useful evidence on the potential of these drugs. In conclusion, this study provides a promising preclinical basis for the further development of GLP-1 receptor agonists for people with Wolfram syndrome. 

To read this study, go to: Gorgogietas V, Rajaei B, Heeyoung C, Santacreu BJ, Marin-Cañas S, Salpea P, Sawatani T, Musuaya A, Arroyo MN, Moreno-Castro C, Benabdallah K, Demarez C, Toivonen S, Cosentinao C, Pachera N, Lytrivi M, Cai Y, Carnel L, Brown C, Urano F, Marchetti P, Cilon P, Eizirik DL, Cnop M, Igoillo-Esteve M. GLP-1R agonists demonstrate potential to treat Wolfram syndrome in preclinical models. Diabetologia 30 March 2023.

To learn more, enrol on the EASD e-Learning course ‘GLP-1 receptor agonists’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.