title: Hematopoietic stem cell-targeted neonatal gene therapy reverses lethally progressive osteopetrosis in oc/oc mice.
abstract: Infantile malignant osteopetrosis (IMO) is a fatal disease caused by lack of functional osteoclasts, and the only available treatment is hematopoietic stem cell (HSC) transplantation. In the majority of patients, the TCIRG1 gene, coding for a subunit of a proton pump essential for bone resorption, is mutated. Oc/oc mice have a deletion in the homologue gene (tcirg1) and die at 3 to 4 weeks, but can be rescued by neonatal transplantation of HSCs. Here, HSC-targeted gene therapy of osteopetrosis in the oc/oc mouse model was developed. Oc/oc fetal liver cells depleted of Ter119-expressing erythroid cells were transduced with a retroviral vector expressing tcirg1 and GFP, and subsequently transplanted intraperitoneally to irradiated neonatal oc/oc mice. Eight of 15 mice survived past the normal life span of oc/oc mice. In vitro osteoclastogenesis revealed formation of GFP-positive osteoclasts and bone resorption, albeit at a lower level than from wild-type cells. The skeletal phenotype was analyzed by X-ray and histopathology and showed partial correction at 8 weeks and almost normalization after 18 weeks. In summary, osteopetrosis in oc/oc mice can be reversed by neonatal transplantation of gene-modified HSCs leading to long-term survival. This represents a significant step toward the development of gene therapy for osteopetrosis.
authors.affiliation: Department of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden.
authors.forename: Maria K
authors.initials: MK
authors.lastname: Johansson
authors.forename: Teun J
authors.initials: TJ
authors.lastname: de Vries
authors.forename: Ton
authors.initials: T
authors.lastname: Schoenmaker
authors.forename: Mats
authors.initials: M
authors.lastname: Ehinger
authors.forename: Ann C M
authors.initials: AC
authors.lastname: Brun
authors.forename: Anders
authors.initials: A
authors.lastname: Fasth
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
authors.forename: Vincent
authors.initials: V
authors.lastname: Everts
authors.forename: Johan
authors.initials: J
authors.lastname: Richter
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D018450:Disease Progression; D015316:Genetic Therapy / Q000379:methods*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D051379:Mice; D008817:Mice, Mutant Strains; D010022:Osteopetrosis / Q000628:therapy*; D017384:Sequence Deletion; D015996:Survival Rate; D025262:Vacuolar Proton-Translocating ATPases / Q000008:administration & dosage* / Q000235:genetics
chemical_list: C484226:Atp6ap1 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases