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GH is secreted by the somatotropic cells of the pituitary gland, and its deficiency (GHD) impairs longitudinal growth. Due to its short half-life, GH therapy needs administration of GH injections daily. Adeno-associated viral vectors (AAV) can deliver gene therapy to animals with possible future applications in humans. The new generation of double-stranded AAV vectors (dsAAV) provides widespread, strong, and stable transgene expression without toxicity and immune response. To determine whether such a new system could be used to deliver GH to a mouse model of isolated GHD due to ablation of the GHRH knock-out gene (GHRHKO), we have created AAV viral particles containing mouse GH cDNA driven by a cytomegalovirus promoter (dsAAV8-CMV-GH), and tested them in male GHRHKO mice. GHRHKO animals received either a single (low dose) or two (high dose) i.p. injections of dsAAV8-CMV-GH (1x10(11) particles) at the 10th and 11th days of age, or a placebo injection, and were followed up to the 6th or 24th week of life. A single dsAAV8-GH injection caused body length and weight normalization. At week 6, serum GH was higher in mice receiving both virus doses compared with controls, while it was normal at week 24. Serum IGF-1 increased in both virus-treated groups, and it was normal at 24 weeks. GH mRNA expression was detected in liver, skeletal, and heart muscle of virus-injected animals. These data show that normalization of longitudinal growth can be reached in GHD mice using a single injection of a double-stranded adeno-associated virus expressing GH.

A single injection of double-stranded adeno-associated viral vector expressing GH normalizes growth in GH-deficient mice