Mandrioli Jessica, D'Amico Roberto, Zucchi Elisabetta, Gessani Annalisa, Fini Nicola, Fasano Antonio, Caponnetto Claudia, Chiò Adriano, Dalla Bella Eleonora, Lunetta Christian, Mazzini Letizia, Marinou Kalliopi, Sorarù Gianni, de Biasi Sara, Lo Tartaro Domenico, Pinti Marcello, Cossarizza Andrea
Department of Neuroscience, St. Agostino-Estense Hospital, Azienda Ospedaliero Universitaria di Modena, University of Modena and Reggio Emilia, Modena Unit of Statistics, Department of Diagnostic, Clinical and Public Health Medicine, University of Modena and Reggio Emilia, Azienda Ospedaliero Universitaria di Modena, Modena Department of Neurosciences, Rehabilitation Ophthalmology, Genetics, Mother and Child Disease, Ospedale Policlinico San Martino, Genova "Rita Levi Montalcini"-Department of Neurosciences, ALS Centre, University of Turin and Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin 3rd Neurology Unit and ALS Centre, IRCCS "Carlo Besta" Neurological Institute, Milan NEuroMuscular Omnicenter, Serena Onlus Foundation, Milan ALS Centre, Neurologic Clinic, Maggiore della Carità University Hospital, Novara ALS Center, "Salvatore Maugeri" Clinical-Scientific Institutes, Milan Department of Neurosciences, University of Padua, Padua, Department of Life Sciences, University of Modena and Reggio Emilia, Modena Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia School of Medicine, Modena, Italy.
Medicine (Baltimore). 2018 Jun;97(24):e11119. doi: 10.1097/MD.0000000000011119.
Misfolded aggregated proteins and neuroinflammation significantly contribute to amyotrophic lateral sclerosis (ALS) pathogenesis, hence representing therapeutic targets to modify disease expression. Rapamycin inhibits mechanistic target of Rapamycin (mTOR) pathway and enhances autophagy with demonstrated beneficial effects in neurodegeneration in cell line and animal models, improving phenotype in SQSTM1 zebrafish, in Drosophila model of ALS-TDP, and in the TDP43 mouse model, in which it reduced neuronal loss and TDP43 inclusions. Rapamycin also expands regulatory T lymphocytes (Treg) and increased Treg levels are associated with slow progression in ALS patients.Therefore, we planned a randomized clinical trial testing Rapamycin treatment in ALS patients.
RAP-ALS is a phase II randomized, double-blind, placebo-controlled, multicenter (8 ALS centers in Italy), clinical trial. The primary aim is to assess whether Rapamycin administration increases Tregs number in treated patients compared with control arm. Secondary aims include the assessment of safety and tolerability of Rapamycin in patients with ALS; the minimum dosage to have Rapamycin in cerebrospinal fluid; changes in immunological (activation and homing of T, B, NK cell subpopulations) and inflammatory markers, and on mTOR downstream pathway (S6RP phosphorylation); clinical activity (ALS Functional Rating Scale-Revised, survival, forced vital capacity); and quality of life (ALSAQ40 scale).
Rapamycin potentially targets mechanisms at play in ALS (i.e., autophagy and neuroinflammation), with promising preclinical studies. It is an already approved drug, with known pharmacokinetics, already available and therefore with significant possibility of rapid translation to daily clinics. Findings will provide reliable data for further potential trials.
The study protocol was approved by the Ethics Committee of Azienda Ospedaliero Universitaria of Modena and by the Ethics Committees of participating centers (Eudract n. 2016-002399-28) based on the Helsinki declaration.
错误折叠的聚集蛋白和神经炎症在肌萎缩侧索硬化症（ALS）的发病机制中起重要作用，因此是改变疾病表现的治疗靶点。雷帕霉素抑制雷帕霉素机制性靶点（mTOR）通路并增强自噬，在细胞系和动物模型的神经退行性变中显示出有益作用，改善了SQSTM1斑马鱼、ALS-TDP果蝇模型和TDP43小鼠模型的表型，其中它减少了神经元损失和TDP43包涵体。雷帕霉素还能扩增调节性T淋巴细胞（Treg），而ALS患者中Treg水平升高与疾病进展缓慢有关。因此，我们计划进行一项随机临床试验，测试雷帕霉素对ALS患者的治疗效果。
RAP-ALS是一项II期随机、双盲、安慰剂对照、多中心（意大利8个ALS中心）临床试验。主要目的是评估与对照组相比，给予雷帕霉素治疗的患者体内Treg数量是否增加。次要目的包括评估雷帕霉素在ALS患者中的安全性和耐受性；脑脊液中出现雷帕霉素的最小剂量；免疫（T、B、NK细胞亚群的激活和归巢）和炎症标志物以及mTOR下游通路（S6RP磷酸化）的变化；临床活性（修订的ALS功能评定量表、生存率、用力肺活量）；以及生活质量（ALSAQ40量表）。
雷帕霉素可能靶向ALS中起作用的机制（即自噬和神经炎症），临床前研究前景良好。它是一种已获批的药物，具有已知的药代动力学，已可获得，因此有很大可能迅速应用于日常临床。研究结果将为进一步的潜在试验提供可靠数据。
该研究方案已获得摩德纳大学医院伦理委员会以及参与中心伦理委员会（Eudract编号：2016-002399-28）根据赫尔辛基宣言的批准。
