Most lysosomal storage diseases (LSDs) involve progressive central nervous system (CNS) impairment, resulting from deficiency of a lysosomal enzyme. Treatment of neuronopathic LSDs remains a considerable challenge, as approved intravenously administered enzyme therapies are ineffective in modifying CNS disease because they do not effectively cross the blood-brain barrier (BBB). We describe a therapeutic platform for increasing the brain exposure of enzyme replacement therapies. The enzyme transport vehicle (ETV) is a lysosomal enzyme fused to an Fc domain that has been engineered to bind to the transferrin receptor, which facilitates receptor-mediated transcytosis across the BBB. We demonstrate that ETV fusions containing iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II, exhibited high intrinsic activity and degraded accumulated substrates in both IDS-deficient cell and in vivo models. ETV substantially improved brain delivery of IDS in a preclinical model of disease, enabling enhanced cellular distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a reduction in accumulated substrates in these CNS cell types and peripheral tissues and resulted in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuroaxonal damage. These data highlight the therapeutic potential of the ETV platform for LSDs and provide preclinical proof of concept for TV-enabled therapeutics to treat CNS diseases more broadly.

大多数溶酶体贮积病 (LSD) 涉及进行性中枢神经系统 (CNS) 损伤，这是由于溶酶体酶缺乏所致。神经元性 LSD 的治疗仍然是一个相当大的挑战，因为批准的静脉内给药的酶疗法在改善 CNS 疾病方面无效，因为它们不能有效地穿过血脑屏障 (BBB)。我们描述了一个治疗平台，用于增加酶替代疗法的大脑暴露。酶转运载体 (ETV) 是一种与 Fc 结构域融合的溶酶体酶，该 Fc 结构域已被设计为与转铁蛋白受体结合，从而促进受体介导的跨 BBB 的胞吞作用。我们证明了含有艾杜糖醛酸 2-硫酸酯酶 (ETV:IDS) 的 ETV 融合体，II 型粘多糖贮积症中缺乏溶酶体酶，在 IDS 缺陷细胞和体内模型中均表现出高内在活性和降解积累的底物。ETV 在疾病的临床前模型中显着改善了 IDS 的大脑传递，从而增强了整个大脑中神经元、星形胶质细胞和小胶质细胞的细胞分布。改善 ETV 的大脑暴露：IDS 转化为这些 CNS 细胞类型和外周组织中积累的底物减少，并导致大脑中下游疾病相关病理的完全纠正，包括溶酶体脂质的继发性积累、基因表达紊乱、神经炎症, 和神经轴索损伤。这些数据突出了 ETV 平台对 LSD 的治疗潜力，并为电视支持疗法提供了更广泛治疗 CNS 疾病的概念的临床前证明。