Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854, USA.
Mol Ther. 2011 Oct;19(10):1842-8. doi: 10.1038/mt.2011.130. Epub 2011 Jul 5.
Late infantile neuronal ceroid lipofuscinosis (LINCL) is a progressive neurodegenerative lysosomal storage disorder caused by mutations in TPP1, the gene encoding the lysosomal protease tripeptidyl-peptidase (TPP1). LINCL primarily affects children, is fatal and there is no effective treatment. Administration of recombinant protein has proved effective in treatment of visceral manifestations of other lysosomal storage disorders but to date, only marginal improvement in survival has been obtained for neurological diseases. In this study, we have developed and optimized a large-volume intrathecal administration strategy to deliver therapeutic amounts of TPP1 to the central nervous system (CNS) of a mouse model of LINCL. To determine the efficacy of treatment, we have monitored survival as the primary endpoint and demonstrate that an acute treatment regimen (three consecutive daily doses started at 4 weeks of age) increases median lifespan of the LINCL mice from 16 (vehicle treated) to 23 weeks (enzyme treated). Consistent with the increase in life-span, we also observed significant reversal of pathology and improvement in neurological phenotype. These results provide a strong basis for both clinical investigation of large-volume/high-dose delivery of TPP1 to the brain via the cerebrospinal fluid (CSF) and extension of this approach towards other neurological lysosomal storage diseases.
晚期婴儿神经元蜡样脂褐质沉积症（LINCL）是一种进行性神经退行性溶酶体贮积症，由编码溶酶体蛋白酶三肽基肽酶（TPP1）的基因 TPP1 突变引起。LINCL 主要影响儿童，是致命的，目前尚无有效的治疗方法。重组蛋白的给药已被证明对其他溶酶体贮积症的内脏表现有效，但迄今为止，神经疾病的生存仅得到了轻微改善。在这项研究中，我们开发并优化了大容量鞘内给药策略，以将治疗剂量的 TPP1 递送至 LINCL 小鼠模型的中枢神经系统（CNS）。为了确定治疗效果，我们将存活作为主要终点进行监测，并证明急性治疗方案（从 4 周龄开始连续三天给予三次剂量）可将 LINCL 小鼠的中位寿命从 16 周（用载体治疗）延长至 23 周（用酶治疗）。与寿命延长一致，我们还观察到病理的显著逆转和神经表型的改善。这些结果为通过脑脊液（CSF）向大脑进行大容量/高剂量 TPP1 输送的临床研究以及将这种方法扩展到其他神经溶酶体贮积病提供了强有力的依据。
