title: Partial rescue of growth failure in growth hormone (GH)-deficient mice by a single injection of a double-stranded adeno-associated viral vector expressing the GH gene driven by a muscle-specific regulatory cassette.
abstract: Growth hormone (GH) deficiency (GHD) causes somatic growth impairment. GH has a short half-life and therefore it must be administered by daily subcutaneous injections. Adeno-associated viral (AAV) vectors have been used to deliver genes to animals, and double-stranded AAV (dsAAV) vectors provide widespread and stable transgene expression. In the present study we tested whether an intramuscular injection of dsAAV vector expressing GH under the control of a muscle creatine kinase regulatory cassette would ensure sufficient systemic GH delivery in conjunction with muscle-specific expression. Virus-injected GHD mice showed a significant (p < 0.05) increase in body length and body weight, without reaching full normalization, and significant (p < 0.05) reduction in absolute and relative visceral fat. Quantitative RT-PCR showed preferential GH expression in skeletal muscles that was confirmed by qualitative fluorescence analysis in mice injected with a similar virus expressing green fluorescent protein. The present study shows that systemic GH delivery to GHD animals is possible via a single intramuscular injection of dsAAV carrying a muscle-specific GH-expressing regulatory cassette.
authors.affiliation: Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Martari
authors.forename: Alessia
authors.initials: A
authors.lastname: Sagazio
authors.forename: Ali
authors.initials: A
authors.lastname: Mohamadi
authors.forename: Quynh
authors.initials: Q
authors.lastname: Nguyen
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hauschka
authors.forename: Eun
authors.initials: E
authors.lastname: Kim
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvatori
mesh_terms: D000818:Animals; D001823:Body Composition; D001835:Body Weight; D000229:Dependovirus / Q000235:genetics*; D005269:Femur / Q000473:pathology; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D013006:Growth Hormone / Q000097:blood / Q000172:deficiency / Q000235:genetics* / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D009132:Muscles / Q000473:pathology*; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D013977:Tibia / Q000473:pathology
chemical_list: D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone