Oligonucleotide-based gene correction strategies: applications to neuromuscular and cardiovascular diseases

Gene augmentation is an attractive and viable approach in treatment of inherited diseases, despite its limitations, ie, the amount of viral genome in replication-defective viral vectors is often too small for larger copy DNAs to be inserted. In addition, most viral vectors, when assessed in vivo, can elicit a host immune response, especially in cases of introduction of a gene copy where protein is completely absent, may have potential mutagenic effect on the host genome, or may be down-regulated. Therefore, alternative therapeutic approaches are being investigated, such as chimeraplasty, in which a mutated allele that already exists in an affected individual can be corrected. Although the only gene defects that can be corrected by chimeraplasty are point mutations, and the correction frequencies are variable, it has been observed that intracellular delivery of oligonucleotides is likely to be more efficient than that of plasmid DNA or viral vectors, because corrected genes are expressed from their autologous promoters, ensuring thus correct spatial and temporal expression, and host immune response is not elicited. Another strategy in the therapy of inherited diseases, such as Duchenne muscular dystrophy, is the application of antisense RNA oligonucleotides, or splicomers, to the exclusion of exons whose mutation leads to production of deficient essential proteins. Here we report the recent progress made and problems encountered in each of these fields, and discuss the potential of nucleotide-based gene correction strategies in treatment of neuromuscular and cardiovascular diseases.