PDF(Pubmed)
Abstract：
Aims: Wolfram syndrome type 1 is a rare recessive monogenic form of insulin-dependent diabetes mellitus with progressive neurodegeneration, poor prognosis, and no cure. Based on preclinical evidence we hypothesized that liraglutide, a glucagon-like peptide-1 receptor agonist, may be repurposed for the off-label treatment of Wolfram Syndrome type 1. We initiated an off-label treatment to investigate the safety, tolerability, and efficacy of liraglutide in pediatric patients with Wolfram Syndrome type 1. Methods: Pediatric patients with genetically confirmed Wolfram Syndrome type 1 were offered off-label treatment approved by The Regional Network Coordination Center for Rare Diseases, Pharmacological Research IRCCS Mario Negri, and the internal ethics committee. Four patients were enrolled; none refused nor were excluded or lost during follow-up. Liraglutide was administered as a daily subcutaneous injection. Starting dose was 0.3 mg/day. The dose was progressively increased as tolerated, up to the maximum dose of 1.8 mg/day. The primary outcome was evaluating the safety, tolerability, and efficacy of liraglutide in Wolfram Syndrome type 1 patients. Secondary endpoints were stabilization or improvement of C-peptide secretion as assessed by the mixed meal tolerance test. Exploratory endpoints were stabilization of neurological and neuro-ophthalmological degeneration, assessed by optical coherence tomography, electroretinogram, visual evoked potentials, and magnetic resonance imaging. Results: Four patients aged between 10 and 14 years at baseline were treated with liraglutide for 8-27 months. Liraglutide was well-tolerated: all patients reached and maintained the maximum dose, and none withdrew from the study. Only minor transient gastrointestinal symptoms were reported. No alterations in pancreatic enzymes, calcitonin, or thyroid hormones were observed. At the latest follow-up, the C-peptide area under the curve ranged from 81 to 171% of baseline. Time in range improved in two patients. Neuro-ophthalmological and neurophysiological disease parameters remained stable at the latest follow-up. Conclusions: We report preliminary data on the safety, tolerability, and efficacy of liraglutide in four pediatric patients with Wolfram Syndrome type 1. The apparent benefits both in terms of residual C-peptide secretion and neuro-ophthalmological disease progression warrant further studies on the repurposing of glucagon-like peptide-1 receptor agonists as disease-modifying agents for Wolfram Syndrome type 1.
摘要：
目的：1型Wolfram综合征是一种罕见的隐性单基因形式的胰岛素依赖型糖尿病，伴有进行性神经变性，预后不良,也无法治愈.根据临床前证据，我们假设利拉鲁肽，胰高血糖素样肽-1受体激动剂，可能会重新用于1型Wolfram综合征的标签外治疗。我们启动了一项标签外治疗，以调查安全性，耐受性,利拉鲁肽在Wolfram综合征1型患儿中的疗效。方法:对基因确诊的Wolfram综合征1型的儿科患者提供由罕见疾病区域网络协调中心批准的超标签治疗,药理学研究IRCCS马里奥·内格里，还有内部道德委员会.招募了四名患者；随访期间没有拒绝，也没有排除或丢失。利拉鲁肽作为每日皮下注射施用。起始剂量为0.3mg/天。随着耐受，剂量逐渐增加，高达1.8毫克/天的最大剂量。主要结果是评估安全性，耐受性,利拉鲁肽在1型Wolfram综合征患者中的疗效。次要终点是通过混合膳食耐受性测试评估的C肽分泌的稳定或改善。探索性终点是神经和神经眼科变性的稳定，通过光学相干断层扫描评估，视网膜电图,视觉诱发电位,和磁共振成像。结果：基线时年龄在10至14岁之间的四名患者接受了利拉鲁肽治疗8-27个月。利拉鲁肽耐受性良好：所有患者均达到并维持最大剂量，没有人退出研究。仅报告了轻微的短暂胃肠道症状。胰腺酶没有改变,降钙素,或观察到甲状腺激素。在最新的后续行动中，曲线下C肽面积为基线的81~171%.两名患者的时间范围内改善。在最新的随访中，神经眼科和神经生理学疾病参数保持稳定。结论：我们报告了有关安全性的初步数据，耐受性,利拉鲁肽对4例1型Wolfram综合征患儿的疗效。在残留C肽分泌和神经眼科疾病进展方面的明显益处值得进一步研究胰高血糖素样肽1受体激动剂作为1型Wolfram综合征的疾病修饰剂的用途。
