Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
Eye Clinic of Tartu University Hospital, Tartu, Estonia.
Front Endocrinol (Lausanne). 2023 Oct 13;14:1234925. doi: 10.3389/fendo.2023.1234925. eCollection 2023.
Wolfram Syndrome (WS) is a rare condition caused by mutations in , 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.
Eight-month-old 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.
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.
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.
Wolfram 综合征（WS）是一种由 基因突变引起的罕见疾病，预后不良，尚无治愈方法。针对肠促胰岛素胰高血糖素样肽 1（GLP-1）的单激动剂在临床前和临床环境中显示出了疾病修饰潜力。据报道，同时靶向 GLP-1 和葡萄糖依赖性胰岛素释放肽 1（GIP-1）的双重激动剂更有效；因此，我们评估了双重肠促胰岛素激动剂在 WS 功能丧失型大鼠模型中的治疗潜力。
连续四个月，给 8 月龄的 敲除（KO）和野生型对照大鼠用双重激动剂 DA-CH5 或生理盐水治疗。在治疗前、10.5 个月和 12 个月时，进行血糖谱、视力和听力敏感性的纵向监测。采集胰腺和视网膜进行免疫组织化学分析。
DA-CH5 治疗逆转了 KO 大鼠的葡萄糖不耐受，并提供了持久的抗糖尿病保护作用。治疗还逆转了胰岛内的改变，包括减少内分泌胰岛面积和β细胞密度，表明其具有再生潜力。尽管对听力损失没有挽救作用，但在接受 DA-CH5 治疗的大鼠中，视力和视网膜神经节细胞密度得到了更好的保留。
我们提出了长期双重肠促胰岛素激动剂治疗的多效治疗效果的临床前证据；尽管治疗开始于症状出现后，但仍观察到效果，表明疾病进展得到逆转。双重肠促胰岛素为 WS 患者提供了一种有前途的治疗途径。
