title: Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells.
abstract: Protective protein/cathepsin A (PPCA), a lysosomal carboxypeptidase, is deficient in the neurodegenerative lysosomal disorder galactosialidosis (GS). PPCA(-/-) mice display a disease course similar to that of severe human GS, resulting in nephropathy, ataxia, and premature death. Bone marrow transplantation (BMT) in mutant animals using transgenic BM overexpressing the corrective enzyme in either erythroid cells or monocytes/macrophages has proven effective for the improvement of the phenotype, and encouraged the use of genetically modified BM cells for ex vivo gene therapy of GS. Here, we established stable donor hematopoiesis in PPCA(-/-) mice that received hematopoietic progenitors transduced with a murine stem cell virus (MSCV)-based, bicistronic retroviral vector overexpressing PPCA and the green fluorescent protein (GFP) marker. We observed complete correction of the disease phenotype in the systemic organs up to 10 months after transplantation. PPCA(+) BM-derived cells were detected in all tissues, with the highest expression in liver, spleen, BM, thymus, and lung. In addition, a lysosomal immunostaining was seen in nonhematopoietic cells, indicating efficient uptake of the corrective protein by these cells and cross-correction. Expression in the brain occurred throughout the parenchyma but was mainly localized on perivascular areas. However, PPCA expression in the central nervous system was apparently sufficient to delay the onset of Purkinje cell degeneration and to correct the ataxia. The long-term expression and internalization of the PPCA by cells of systemic organs and the clear improvement of the neurologic phenotype support the use of this approach for the treatment of GS in humans. (Blood. 2002;99:3169-3178)
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Thasia
authors.initials: T
authors.lastname: Leimig
authors.forename: Linda
authors.initials: L
authors.lastname: Mann
authors.forename: Maria del Pilar
authors.initials: Mdel P
authors.lastname: Martin
authors.forename: Erik
authors.initials: E
authors.lastname: Bonten
authors.forename: Derek
authors.initials: D
authors.lastname: Persons
authors.forename: James
authors.initials: J
authors.lastname: Knowles
authors.forename: James A
authors.initials: JA
authors.lastname: Allay
authors.forename: John
authors.initials: J
authors.lastname: Cunningham
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Nienhuis
authors.forename: Richard
authors.initials: R
authors.lastname: Smeyne
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
mesh_terms: D000818:Animals; D001259:Ataxia / Q000209:etiology / Q000628:therapy; D001854:Bone Marrow Cells / Q000166:cytology; D002268:Carboxypeptidases / Q000008:administration & dosage / Q000235:genetics / Q000493:pharmacokinetics; D043402:Cathepsin A; D002493:Central Nervous System Diseases / Q000209:etiology / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods; D049452:Green Fluorescent Proteins; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007674:Kidney Diseases / Q000209:etiology / Q000628:therapy; D008164:Luminescent Proteins / Q000235:genetics; D016464:Lysosomal Storage Diseases / Q000628:therapy*; D051379:Mice; D018345:Mice, Knockout; D009081:Mucolipidoses / Q000150:complications / Q000473:pathology / Q000628:therapy*; D009439:Neuraminidase / Q000172:deficiency; D009928:Organ Specificity; D014018:Tissue Distribution; D016896:Treatment Outcome; D001616:beta-Galactosidase / Q000172:deficiency
chemical_list: D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D009439:Neuraminidase; D001616:beta-Galactosidase; D002268:Carboxypeptidases; D043402:Cathepsin A