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

Front Endocrinol (Lausanne). 2023 Oct 13;14:1234925. doi: 10.3389/fendo.2023.1234925. eCollection 2023.


AIM: Wolfram 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.

METHODS: Eight-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.

RESULTS: DA-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.

CONCLUSION: We 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.

PMID:37900147 | PMC:PMC10611518 | DOI:10.3389/fendo.2023.1234925