Frontino Giulio, Raouf Tara, Canarutto Daniele, Tirelli Eva, Di Tonno Raffaella, Rigamonti Andrea, Cascavilla Maria Lucia, Baldoli Cristina, Scotti Roberta, Leocani Letizia, Huang Su-Chun, Meschi Franco, Barera Graziano, Broccoli Vania, Rossi Greta, Torchio Silvia, Chimienti Raniero, Bonfanti Riccardo, Piemonti Lorenzo
Department of Pediatrics, IRCCS San Raffaele Hospital, Milan, Italy.
Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, Italy.
Front Pediatr. 2021 Dec 14;9:755365. doi: 10.3389/fped.2021.755365. eCollection 2021.
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. 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. 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. 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.
1型沃尔弗拉姆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，伴有进行性神经退行性变，预后不良且无法治愈。基于临床前证据，我们推测胰高血糖素样肽-1受体激动剂利拉鲁肽可能可重新用于1型沃尔弗拉姆综合征的非标签治疗。我们启动了一项非标签治疗，以研究利拉鲁肽在1型沃尔弗拉姆综合征儿科患者中的安全性、耐受性和疗效。经罕见病区域网络协调中心、药理研究IRCCS马里奥·内格里研究所和内部伦理委员会批准，为基因确诊的1型沃尔弗拉姆综合征儿科患者提供非标签治疗。招募了4名患者；在随访期间，无人拒绝、被排除或失访。利拉鲁肽通过每日皮下注射给药。起始剂量为0.3毫克/天。剂量根据耐受性逐渐增加，直至最大剂量1.8毫克/天。主要结局是评估利拉鲁肽在1型沃尔弗拉姆综合征患者中的安全性、耐受性和疗效。次要终点是通过混合餐耐量试验评估C肽分泌的稳定或改善情况。探索性终点是通过光学相干断层扫描、视网膜电图、视觉诱发电位和磁共振成像评估神经和神经眼科退行性变的稳定情况。4名基线年龄在10至14岁之间的患者接受了利拉鲁肽治疗8至27个月。利拉鲁肽耐受性良好：所有患者均达到并维持了最大剂量，无人退出研究。仅报告了轻微的短暂胃肠道症状。未观察到胰腺酶、降钙素或甲状腺激素的改变。在最近一次随访时，C肽曲线下面积为基线的81%至171%。两名患者的血糖在目标范围内的时间有所改善。在最近一次随访时，神经眼科和神经生理学疾病参数保持稳定。我们报告了利拉鲁肽在4名1型沃尔弗拉姆综合征儿科患者中的安全性、耐受性和疗效的初步数据。在残余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将胰高血糖素样肽-1受体激动剂重新用作1型沃尔弗拉姆综合征的疾病改善药物。
