Rna Splicing Modulation: Therapeutic Progress And Perspectives

Advances in genetic and genomic research continue to increase our knowledge of hereditary diseases, and an increasing number of them are being attributed to aberrant splicing, thus representing ideal targets for RNA modulation therapies. New strategies to skip or re-include exons during the splicing process have emerged and are now widely evaluated in the clinic. Several drugs have recently been approved in particular for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy. Among these molecules, antisense oligonucleotides, or ASOs, have gained increasing interest and have constantly been improved over the years through chemical modifications and design. However, their limited biodistribution following systemic administration still represents a major hurdle and the development of more potent alternative chemistries or new delivery systems has become a very active line of research in the past few years. In parallel, the use of small molecules with excellent biodistribution properties or of viral vectors to convey antisense sequences is also being investigated. In this review, we summarize the recent advances in splicing therapies through two examples of neuromuscular diseases and we discuss their main benefits and current limitations.