On 24 August at 16:00 Kadri Seppa will defend her doctoral thesis “The neuroprotective effect of GLP1 receptor agonist liraglutide in a rat model of Wolfram syndrome”.
Associate Professor Mario Plaas, University of Tartu
Professor Eero Vasar, University of Tartu
Senior Research Fellow Anton Terasmaa, National Institute of Chemical Physics and Biophysics
Professor Tamara Hershey, Washington University (USA)
Wolfram syndrome is a rare hereditary disorder that is caused by biallelic mutations in the WFS1 gene, from which WFS1 (Wolframin) protein is encoded. Wolfram syndrome starts with diabetes mellitus followed by optic nerve atrophy and neurodegeneration. As no effective therapy is available, drug repurposing could be the best therapeutic option because the drugs are already approved and thereby reach patients faster. GLP-1 receptor agonists are used for the treatment of diabetes mellitus and have neuroprotective properties in addition to glucose-lowering effects. Hence, they could also have a potential therapeutic effect for the main symptoms of Wolfram syndrome. In addition to GLP-1 receptor agonists, the neurotrophic factor, such as BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF), has not been studied in connection with Wolfram syndrome. In vivo investigations for drug repurposing would not be possible without well-characterized animal models. Therefore, our research group has created Wfs1 KO rats with an exon 5 disruption. The aim of this dissertation is (i) to evaluate the symptoms of Wolfram syndrome in Wfs1 KO rats and (ii) to use it to test novel treatment strategies for Wolfram syndrome with an emphasis on neurodegeneration. The current thesis demonstrates that Wfs1 KO rats developed the main symptoms of Wolfram syndrome: diabetes mellitus and neurodegeneration. This indicates that the Wfs1 KO rat is indeed a Wolfram syndrome animal model, and it can be used to test treatment strategies for Wolfram syndrome. The anti-diabetic drug liraglutide protected Wfs1 KO rats against development of glucose intolerance. Moreover, liraglutide treatment had a neuroprotective effect in the olive nucleus, as measured by decreased neuroinflammation, ER stress and neuronal swelling. Additionally, BDNF mimetic 7,8-DHF had an anti-inflammatory effect on the hippocampus and maintained cognitive function in Wfs1 KO animals. However, an anti-diabetic effect of 7,8-DHF was not detected. Therefore, liraglutide treatment alone or co-treatment with liraglutide and 7,8-DHF could be promising treatment strategies for Wolfram syndrome patients. Inspired by preclinical studies, a liraglutide clinical trial has been initiated, and further investigations will clarify the effect of liraglutide in Wolfram syndrome patients.