Brain‐targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms

Abstract The pediatric lysosomal storage disorder mucopolysaccharidosis type IIis caused by mutations in IDS, resulting in accumulation of heparan and dermatan sulfate, causing severe neurodegeneration, skeletal disease, and cardiorespiratory disease. Most patients manifest with cognitive symptoms, which cannot be treated with enzyme replacement therapy, as native IDS does not cross the blood–brain barrier. We tested a brain‐targeted hematopoietic stem cellgene therapy approach using lentiviral IDS fused to ApoEII (IDS.ApoEII) compared to a lentivirusexpressing normal IDS or a normal bone marrow transplant. In mucopolysaccharidosis IImice, all treatments corrected peripheral disease, but only IDS.ApoEII mediated complete normalization of brain pathology and behavior, providing significantly enhanced correction compared to IDS. A normal bone marrow transplant achieved no brain correction. Whilst corrected macrophages traffic to the brain, secreting IDS/IDS.ApoEII enzyme for cross‐correction, IDS.ApoEII was additionally more active in plasma and was taken up and transcytosed across brain endothelia significantly better than IDS via both heparan sulfate/ApoE‐ dependent receptorsand mannose‐6‐phosphate receptors. Brain‐targeted hematopoietic stem cellgene therapy provides a promising therapy for MPS II patients.