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

Abstract

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.

Cardiac AAV9 Gene Delivery Strategies in Adult Canines: Assessment by Long-term Serial SPECT Imaging of Sodium Iodide Symporter Expression

“…This latter point is of great interest given that the use of the native host's cDNA sequence was demonstrated to be important for long-term expression. 29,30 Our study overexpresses the canine NIS protein in immunocompetent dogs, with long-term expression and activity lasting up to 1 year follow-up. The authors therefore consider the NIS transgene to be relatively nonimmunogenic.…”

A novel gene therapy strategy using secreted multifunctional anti-HIV proteins to confer protection to gene-modified and unmodified target cells

“…evaluated for the treatment of other diseases, such as erythropoietin deficiency, a-1 antitrypsin deficiency, hemophilia A and Duchenne muscular dystrophy. [73][74][75][76] Skin and muscle tissues are readily accessible and are highly vascularized, making them suitable for systemic delivery of therapeutic proteins via circulation. Indeed, serum levels of therapeutic proteins reached 1000 mg ml À 1 in vivo.…”

An AAV Vector for Inducible Gene Expression Preferentially in Muscles

“…Different AAV serotypes recognize distinct cell receptors and therefore display specific tissue tropism [25,39]. AAV6 and AAV9 serotypes were previously reported to exhibit tropism for the skeletal muscle and heart tissues by different groups [40][41][42][43]. In addition, for better muscle tissue targeting, Xiao et.…”