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

The pediatric lysosomal storage disorder mucopolysaccharidosis type II is 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 cell gene therapy approach using lentiviral IDS fused to ApoEII (IDS.ApoEII) compared to a lentivirus expressing normal IDS or a normal bone marrow transplant. In mucopolysaccharidosis II mice, 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 receptors and mannose‐6‐phosphate receptors. Brain‐targeted hematopoietic stem cell gene therapy provides a promising therapy for MPS II patients. Synopsis The use of an ApoEII‐tag to increase uptake of the lysosomal enzyme IDS greatly improved the efficacy of hematopoietic stem cell gene therapy in MPS II mice, providing encouraging therapeutic promise to treat the severe neurodegeneration seen in MPS II patients, for which there is currently no cure. Lentiviral mediated delivery of IDS.ApoEII following hematopoietic stem cell gene therapy was superior to delivery of unmodified IDS. LV.IDS.ApoEII increased IDS enzyme activity in non‐hematopoietic organs and restored normal skeletal development. IDS.ApoEII delivered into the brain of MPS II mice through corrected monocyte‐derived macrophages normalized lysosomal storage of glycosaminoglycans and restored glycosaminoglycan sulfation patterning. IDS.ApoEII rectified behavioral abnormalities and corrected global neuro‐inflammation and neuro‐pathology. IDS.ApoEII shows increased uptake and transcytosis by brain endothelial cells. Graphical Abstract The use of an ApoEII‐tag to increase uptake of the lysosomal enzyme IDS greatly improved the efficacy of hematopoietic stem cell gene therapy in MPS II mice, providing encouraging therapeutic promise to treat