Brain delivery and efficacy of a lysosomal enzyme using a blood-brain barrier transport vehicle [RNA-seq]

The enzyme transport vehicle (ETV:IDS) is a lysosomal enzyme fused to iduronate 2-sulfatase (ETV:IDS), the lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II). ETV:IDS treatment significantly improved brain delivery of IDS in a preclinical model of disease, enabling enhanced distribution to neurons, astrocytes, and microglia throughout the brain. Improved brain exposure for ETV:IDS translated to a significant reduction in accumulated substrates in these CNS cell types and peripheral tissues, and in a complete correction of downstream disease-relevant pathologies in the brain, including secondary accumulation of lysosomal lipids, perturbed gene expression, neuroinflammation, and neuronal injury. These results highlight the therapeutic potential of the ETV approach as a new treatment paradigm for MPS II and for other CNS diseases more broadly. Cells from mice of two genotypes (TfR KI, IDS KO/TfR KO), treated with either vehicle of ETV:IDS were isolated using fluorescent activated cell sorting.