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An erythroid-specific hybrid promoter provided inducible IDUA expression and release during in vitro erythroid differentiation in murine erythroleukemia cells, resulting in phenotypical cross-correction in an enzyme-deficient lymphoblastoid cell line derived from patients with mucopolysaccharidosis type I (MPS I). Stable and higher than normal plasma IDUA levels were achieved in vivo in primary and secondary MPS I chimeras for at least 9 months after transplantation of HSCs transduced with the erythroid-specific IDUA-containing lentiviral vector (LV). Moreover, long-term metabolic correction was demonstrated by normalized urinary glycosaminoglycan accumulation in all treated MPS I mice. Complete normalization of tissue pathology was observed in heart, liver, and spleen. Notably, neurological function and brain pathology were significantly improved in MPS I mice by erythroid-derived, higher than normal peripheral IDUA protein. These data demonstrate that late-stage erythroid cells, transduced with a tissue-specific LV, can deliver a lysosomal enzyme continuously at supraphysiological levels to the bloodstream and can correct the disease phenotype in both viscera and CNS of MPS I mice. This approach provides a paradigm for the utilization of RBC precursors as a depot for efficient and potentially safer systemic delivery of nonsecreted proteins by ex vivo HSC gene transfer.<\/jats:p>","DOI":"10.1073\/pnas.0908528106","type":"journal-article","created":{"date-parts":[[2009,11,10]],"date-time":"2009-11-10T23:29:50Z","timestamp":1257895790000},"page":"19958-19963","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":46,"title":["Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome"],"prefix":"10.1073","volume":"106","author":[{"given":"Daren","family":"Wang","sequence":"first","affiliation":[{"name":"Molecular and Gene Therapy Program, Division of Experimental Hematology and Cancer Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Molecular and Gene Therapy Program, Division of Experimental Hematology and Cancer Biology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodosia A.","family":"Kalfa","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology,"},{"name":"Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45221"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Grabowski","sequence":"additional","affiliation":[{"name":"Division of Human Genetics, and"},{"name":"Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45221"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Davies","sequence":"additional","affiliation":[{"name":"Division of Bone Marrow Transplantation and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; and"},{"name":"Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45221"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Punam","family":"Malik","sequence":"additional","affiliation":[{"name":"Molecular and Gene Therapy Program, Division of Experimental Hematology and Cancer Biology,"},{"name":"Division of Hematology\/Oncology,"},{"name":"Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45221"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dao","family":"Pan","sequence":"additional","affiliation":[{"name":"Molecular and Gene Therapy Program, Division of Experimental Hematology and Cancer Biology,"},{"name":"Department of Pediatrics, University of Cincinnati School of Medicine, Cincinnati, OH 45221"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,11,24]]},"reference":[{"key":"e_1_3_3_1_2","first-page":"381","article-title":"The mucopolysaccharidoses. 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