Department of Pediatrics, Washington University in St. Louis, School of Medicine, St. Louis, Missouri, USA.
The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush Campus, Easter Bush, Scotland, United Kingdom.
J Clin Invest. 2022 Oct 17;132(20):e163107. doi: 10.1172/JCI163107.
CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1-/-) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1-/- mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.
CLN1 病，又称婴儿神经元蜡样脂褐质沉积症（NCL）或婴儿巴滕病，是一种致命的神经退行性溶酶体贮积症，由 CLN1 基因突变引起，该基因突变编码溶酶体可溶性酶棕榈酰蛋白硫酯酶 1（PPT1）。CLN1 病的治疗极具挑战性，原因是疾病进展迅速，需要治疗大脑和脊髓的广泛区域。事实上，基因治疗对 CLN1 病的疗效不如其他类似的溶酶体酶缺乏症。因此，我们通过对 PPT1 缺乏型小鼠（Cln1-/-）和 CLN1R151X 绵羊进行每月重组人 PPT1（rhPPT1）输注，测试了酶替代疗法（ERT）的疗效，以评估如何潜在地扩大规模用于转化。在 Cln1-/-小鼠中，脑内（i.c.v.）rhPPT1 给药是最有效的给药途径，导致中枢神经系统（CNS）中具有治疗相关性的 PPT1 活性。rhPPT1 治疗的小鼠运动功能得到改善，疾病相关病理减少，神经元丢失减少。在 CLN1R151X 绵羊中，i.c.v. 输注导致广泛的 rhPPT1 分布和通过定量结构 MRI 和神经病理学测量的阳性治疗效果。这项研究证明了 i.c.v. rhPPT1 ERT 的可行性和治疗效果。这些发现代表了在 CLN1 病患儿中进行 ERT 临床测试的重要一步，并强调了采用跨物种方法制定成功治疗策略的重要性。
