Regulated production of proteins from muscle using gene transfer: potential therapeutic applications

The ability to produce high-level transgene expression following the introduction of genetic material into a host cell has been well documented. Various vectors and methods for in vivo gene delivery have been shown to provide long-term expression from many different tissue types in rodents and large animals. However, many potential therapeutic targets for gene therapy involve the production of proteins that are toxic or lead to undesirable effects if overexpressed. Thus, the ability to achieve regulated gene expression following treatment will be required to ensure the safety of long-acting gene therapy products. Skeletal muscle, in particular, has been widely used as a target for gene therapy protocols, due to the ease of accessibility and ability to produce and secrete some proteins at very high levels. This review focuses on regulated gene therapy systems that are being evaluated for use in muscle, and discusses two classes of system: those dependent on exogenously administered drugs and those dependent on endogenously produced metabolites.