Somatic gene therapy is expected to provide new and improved therapies for many diseases. GENEMEDICINE, INC. is developing a new class of DNA-based therapeutics, """"""""gene medicines"""""""", which are expected to provide unique clinical benefits for the treatment of a broad range of diseases. Gene medicines utilize tissue-specific DNA expression vectors and novel vector delivery systems for the in vivo delivery of therapeutic proteins. Clinically effective and safe gene medicines will require the development of reliable methods to regulate gene expression such that synthesis of the therapeutic protein is not only restricted to the proper cell-type and tissue but is also at a level that remains within the therapeutic range appropriate for the disease being treated. Previous work at GENEMEDICINE and in the founder's laboratories has led to the development of a muscle- specific vector system (MVS) capable of directing the synthesis of proteins in muscle in vivo. The control of gene expression in eukaryotic cells is complex, involving the interaction of a variety of tissue- specific positive and negative trans-acting protein factors with specific regulatory sequences associated with tissue-regulated genes. MVS vectors incorporate upstream and downstream regulatory sequences derived from the well-characterized chicken skeletal alpha-actin gene to control the expression, mRNA stability and translation of clinically relevant proteins. The purpose of the proposed research is to develop synthetic muscle-specific vectors which will provide higher levels of expression in mammalian muscle cells than natural promoter elements. We will construct a series of synthetic promoter/enhancer fragments based on the sequences of transcriptional control elements involved in the activation and regulation of genes in mammalian muscle cells.
