title: Highly efficient EIAV-mediated in utero gene transfer and expression in the major muscle groups affected by Duchenne muscular dystrophy.
abstract: Gene therapy for Duchenne muscular dystrophy has so far not been successful because of the difficulty in achieving efficient and permanent gene transfer to the large number of affected muscles and the development of immune reactions against vector and transgenic protein. In addition, the prenatal onset of disease complicates postnatal gene therapy. We have therefore proposed a fetal approach to overcome these barriers. We have applied beta-galactosidase expressing equine infectious anaemia virus (EIAV) lentiviruses pseudotyped with VSV-G by single or combined injection via different routes to the MF1 mouse fetus on day 15 of gestation and describe substantial gene delivery to the musculature. Highly efficient gene transfer to skeletal muscles, including the diaphragm and intercostal muscles, as well as to cardiac myocytes was observed and gene expression persisted for at least 15 months after administration of this integrating vector. These findings support the concept of in utero gene delivery for therapeutic and long-term prevention/correction of muscular dystrophies and pave the way for a future application in the clinic.
authors.affiliation: Gene Therapy Research Group, Sir Alexander Fleming Building, Imperial College, South Kensington, London, UK.
authors.forename: L G
authors.initials: LG
authors.lastname: Gregory
authors.forename: S N
authors.initials: SN
authors.lastname: Waddington
authors.forename: M V
authors.initials: MV
authors.lastname: Holder
authors.forename: K A
authors.initials: KA
authors.lastname: Mitrophanous
authors.forename: S M K
authors.initials: SM
authors.lastname: Buckley
authors.forename: K L
authors.initials: KL
authors.lastname: Mosley
authors.forename: B W
authors.initials: BW
authors.lastname: Bigger
authors.forename: F M
authors.initials: FM
authors.lastname: Ellard
authors.forename: L E
authors.initials: LE
authors.lastname: Walmsley
authors.forename: L
authors.initials: L
authors.lastname: Lawrence
authors.forename: F
authors.initials: F
authors.lastname: Al-Allaf
authors.forename: S
authors.initials: S
authors.lastname: Kingsman
authors.forename: C
authors.initials: C
authors.lastname: Coutelle
authors.forename: M
authors.initials: M
authors.lastname: Themis
mesh_terms: D000818:Animals; D005260:Female; D005333:Fetus / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D004860:Infectious Anemia Virus, Equine / Q000235:genetics*; D007267:Injections; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism*; D020388:Muscular Dystrophy, Duchenne / Q000196:embryology / Q000628:therapy*; D011247:Pregnancy; D001616:beta-Galactosidase / Q000235:genetics*
chemical_list: D001616:beta-Galactosidase