By Mario Plaas and Anton Terasmaa
Wfs1 KO rats. These rats were used for 5 months long Liraglutide experiment.
At University of Tartu we have created and characterized Wfs1 knock-out (Wfs1 KO) rat, which exhibits symptoms of Wolfram syndrome (WS), including diabetes mellitus, optic atrophy and degeneration of brainstem [1]. Thus, rat model mimics human condition, is well suited to study molecular mechanism of WS and to evaluate pharmacological treatment strategies. Our activities are mostly related to evaluation of pharmacological treatments in rat model of WS. While performing this work we also try to understand the molecular pathology of WS using histological and molecular biology methods.
We have evaluated effect of GLP1 receptor agonist Liraglutide in the rat model of WS. One week treatment with GLP1 receptor agonist markedly improved diabetic phenotype of these rats. We therefore have tested the effect of 5 months long treatment with GLP1 RA Liraglutide in Wfs1 KO rat, this treatment resulted in an improvement of diabetic phenotype, reduction of ER stress levels and preservation of remaining beta cell mass [2]. Our next study was aimed at evaluation of neuroprotective effects of Liraglutide in the rat model of WS. For this purpose older Wfs1 KO rats were treated with liraglutide for 6 months. Thereafter, number on neurons was evaluated in the brainstem and retina of these rats using stereology. We expect to publish the results of this study very soon.
In parallel, using similar tactics as with Liraglutide, we are evaluating also alternative pharmacological treatment options in our rat model of WS. For this purpose we treat animals with promising drug candidates and evaluate their effects on progression of symptoms of WS. This approach could be the fastest way to find and introduce new treatment options.
1. Plaas, M., et al., Wfs1- deficient rats develop primary symptoms of Wolfram syndrome: insulin-dependent diabetes, optic nerve atrophy and medullary degeneration. Sci Rep, 2017. 7(1): p. 10220.
2. Toots, M., et al., Preventive treatment with liraglutide protects against development of glucose intolerance in a rat model of Wolfram syndrome. Sci Rep, 2018. 8(1): p. 10183.
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