Soluble TNF-α receptor secretion from healthy or dystrophic mice after AAV6-mediated muscle gene transfer

• Published in: Gene therapy Vol. 17; no. 11; pp. 1400 - 1410
• Main Authors: Moulay, G, Masurier, C, Bigey, P, Scherman, D, Kichler, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2010; Nature Publishing Group
• Subjects: 631/1647/2300; 631/326/596/2561; 631/61/201; 692/699/1670/1669; Adeno-associated virus; Animals; Antibody response; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cells, Cultured; Dependovirus - genetics; Dependoviruses; Gene Expression; Gene Therapy; Genetic Therapy; Genetic Vectors - genetics; Health aspects; Human Genetics; Humans; Immune response; Inflammation; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Inbred mdx; Muscle, Skeletal - metabolism; Muscular dystrophy; Muscular Dystrophy, Duchenne - metabolism; Muscular Dystrophy, Duchenne - therapy; Nanotechnology; original-article; Patient outcomes; Physiological aspects; Receptors, Tumor Necrosis Factor, Type I - genetics; Receptors, Tumor Necrosis Factor, Type I - metabolism; Transduction, Genetic; Transgenes; Transgenes - genetics; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; France; dystrophic muscle; gene therapy; adeno-associated virus; TNF receptor; immune response
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2010.94

Muscle is an attractive target because it is easily accessible; it also offers a permissive environment for adeno-associated virus (AAV)-mediated gene transfer and has an abundant blood vascular supply providing an efficient transport system for the secretion of proteins. However, gene therapy of dystrophic muscle may be more difficult than that of healthy tissue because of degenerative–regenerative processes, and also because of the inflammatory context. In this study we followed the expression levels of secreted inhibitors of the proinflammatory tumor necrosis factor (TNF) cytokine after intramuscular (i.m.) injection of AAV6 into dystrophic mdx and healthy C57BL/10 mice. We used two chimeric proteins, namely, the human or murine TNF-soluble receptor I fused with the murine heavy immunoglobulin chain. We conducted an AAV6 dose–response study and determined the kinetics of transgene expression. In addition, we followed the antibody response against the transgenes and studied their expression pattern in the muscle. Our results show that transduction efficiency is reduced in dystrophic muscles as compared with healthy ones. Furthermore, we found that the immune response against the secreted protein is stronger in mdx mice. Together, our results underscore that the pathological state of the muscle has to be taken into consideration when designing gene therapy approaches.