Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome

Frontiers in Endocrinology

Endocrinology

Allen Kaasik¹  Eero Vasar²  Mihkel Plaas³  Marko Pastak⁴  Kadri Seppa⁵  Toomas Jagomäe⁵  Nayana Gaur⁵  Riin Reimets⁵  Mario Plaas⁵ 

[1] Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia;Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia;Ear Clinic of Tartu University Hospital, Tartu, Estonia;Eye Clinic of Tartu University Hospital, Tartu, Estonia;Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia;

关键词: wolfram (DIDMOAD) syndrome;    incretin mimetics;    glucose intolerance;    dual incretins;    animal models - rodent;    Wfs1;   

DOI  :  10.3389/fendo.2023.1234925

 received in 2023-06-05, accepted in 2023-09-27,  发布年份 2023

来源: Frontiers

【 摘 要 】

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.

【 授权许可】

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