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.
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.
Martari
Marco
M
Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Sagazio
Alessia
A
Mohamadi
Ali
A
Nguyen
Quynh
Q
Hauschka
Stephen D
SD
Kim
Eun
E
Salvatori
Roberto
R
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
D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone