Rare and Complex Epilepsy Unit, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Piazza S. Onofrio 4, 00165, Rome, Italy.
Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy.
Drugs. 2021 Jan;81(1):101-123. doi: 10.1007/s40265-020-01440-7.
Neuronal ceroid lipofuscinosis (NCLs) is a group of inherited neurodegenerative lysosomal storage diseases that together represent the most common cause of dementia in children. Phenotypically, patients have visual impairment, cognitive and motor decline, epilepsy, and premature death. A primary challenge is to halt and/or reverse these diseases, towards which developments in potential effective therapies are encouraging. Many treatments, including enzyme replacement therapy (for CLN1 and CLN2 diseases), stem-cell therapy (for CLN1, CLN2, and CLN8 diseases), gene therapy vector (for CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN10, and CLN11 diseases), and pharmacological drugs (for CLN1, CLN2, CLN3, and CLN6 diseases) have been evaluated for safety and efficacy in pre-clinical and clinical studies. Currently, cerliponase alpha for CLN2 disease is the only approved therapy for NCL. Lacking is any study of potential treatments for CLN4, CLN9, CLN12, CLN13 or CLN14 diseases. This review provides an overview of genetics for each CLN disease, and we discuss the current understanding from pre-clinical and clinical study of potential therapeutics. Various therapeutic interventions have been studied in many experimental animal models. Combination of treatments may be useful to slow or even halt disease progression; however, few therapies are unlikely to even partially reverse the disease and a complete reversal is currently improbable. Early diagnosis to allow initiation of therapy, when indicated, during asymptomatic stages is more important than ever.
神经元蜡样脂褐质沉积症（NCLs）是一组遗传性神经退行性溶酶体贮积病，共同构成儿童痴呆症的最常见病因。在表型上，患者有视力障碍、认知和运动能力下降、癫痫和早逝。主要挑战是阻止和/或逆转这些疾病，这方面潜在有效疗法的进展令人鼓舞。许多治疗方法，包括酶替代疗法（用于 CLN1 和 CLN2 疾病）、干细胞疗法（用于 CLN1、CLN2 和 CLN8 疾病）、基因治疗载体（用于 CLN1、CLN2、CLN3、CLN5、CLN6、CLN7、CLN10 和 CLN11 疾病）和药理学药物（用于 CLN1、CLN2、CLN3 和 CLN6 疾病），已在临床前和临床研究中评估了其安全性和有效性。目前，用于 CLN2 疾病的 cerliponase alpha 是唯一批准的 NCL 治疗方法。缺乏对 CLN4、CLN9、CLN12、CLN13 或 CLN14 疾病的潜在治疗方法的研究。本综述提供了每个 CLN 疾病的遗传学概述，并讨论了临床前和临床研究中对潜在治疗方法的当前认识。各种治疗干预措施已在许多实验动物模型中进行了研究。联合治疗可能有助于减缓甚至停止疾病进展；然而，很少有治疗方法甚至可能部分逆转疾病，完全逆转目前不太可能。早期诊断以允许在无症状阶段开始治疗（如有指征）比以往任何时候都更加重要。
