PDF(Pubmed)
Abstract：
Metachromatic leukodystrophy (MLD) is a hereditary neurodegenerative disease characterized by demyelination and motor and cognitive impairments due to deficiencies of the lysosomal enzyme arylsulfatase A (ARSA) or the saposin B activator protein (SapB). Current treatments are limited; however, gene therapy using adeno-associated virus (AAV) vectors for ARSA delivery has shown promising results. The main challenges for MLD gene therapy include optimizing the AAV dosage, selecting the most effective serotype, and determining the best route of administration for ARSA delivery into the central nervous system. This study aims to evaluate the safety and efficacy of AAV serotype 9 encoding ARSA (AAV9-ARSA) gene therapy when administered intravenously or intrathecally in minipigs, a large animal model with anatomical and physiological similarities to humans. By comparing these two administration methods, this study contributes to the understanding of how to improve the effectiveness of MLD gene therapy and offers valuable insights for future clinical applications.
摘要：
转移性脑白质营养不良（MLD）是一种遗传性神经退行性疾病，其特征是由于溶酶体酶芳基硫酸酯酶A（ARSA）或saposinB激活蛋白（SapB）的缺乏而导致的脱髓鞘以及运动和认知障碍。目前的治疗方法有限；然而，使用腺相关病毒（AAV）载体进行ARSA递送的基因治疗已显示出有希望的结果。MLD基因治疗的主要挑战包括优化AAV剂量，选择最有效的血清型，并确定ARSA递送至中枢神经系统的最佳给药途径。本研究旨在评估AAV血清型9编码ARSA（AAV9-ARSA）基因疗法在小型猪静脉内或鞘内给药时的安全性和有效性，与人类有解剖学和生理学相似性的大型动物模型。通过比较这两种给药方法，这项研究有助于了解如何提高MLD基因治疗的有效性,并为未来的临床应用提供有价值的见解.
