Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice

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Science Translational Medicine  27 May 2020:
Vol. 12, Issue 545, eaay1163
DOI: 10.1126/scitranslmed.aay1163

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Transport vehicle for CNS therapeutics

Delivering biotherapeutics to the brain is complicated by the presence of the blood-brain barrier (BBB). Kariolis et al. and Ullman et al. developed a transport vehicle (TV) consisting of an Fc fragment engineered to bind to the transferrin receptor, a protein highly expressed at the BBB. Utilizing the TV in the form of an antibody directed against β-secretase enhanced brain delivery and effects in both mice and monkeys following systemic administration. Systemic delivery of a TV fusion with the iduronate 2-sulfatase enzyme was effective at reducing peripheral and central pathologies in a mouse model of mucopolysaccharidosis type II. The TV platform approach potentially offers a treatment for neurological disorders.


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.

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