Exon-skipping therapeutic approach inDuchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a muscle degenerative disorder thatis caused by mutations in DMD which may suppress the assembly ofdystrophin in muscle and thus, make them vulnerable to damage. Mutationscan be large like large deletions or duplications or they can be small likenonsense mutations, small deletions, small insertions, and splice-sitemutations. One of the most common mutations in these patients is an exonmutation from ۴۳ to ۵۵. One of the most encouraging therapeutic strategies isExon-skipping with the goal of restoring the out-of-frame mRNA of DMDpatients and designing antisense sequences that are responsible for excludingsplicing signals in the final mRNA and thus, result in a larger deletion. In thisstudy, out of ۶۱ primary articles searched in PubMed and Google Scholardatabases from ۲۰۱۴ to ۲۰۲۱, ۲۹ articles with DMD, Exon-skipping,Antisense Oligo Nucleotides (AON), peptide-conjugatedPhosphorodiamidate Morpholino Oligomer (PPMO), PhosphorodiamidateMorpholino Oligomer (PMO) were selected and studied. This reviewdescribes an antisense-based exon-skipping approach for DMD, from conceptproof to the first drug on the market. We discuss the challenges to achieving asuccessful exon-skipping therapy and also the latest advances of theinternational community to develop more powerful chemistries and moresophisticated delivery systems so as to extend potency, bioavailability, andsafety. Exon-skipping by PPMO could transmute the treatment of DMDpatients. The main topic of research in Exon-therapy is diminishing thetoxicity and maintaining PPMO activity. However, further studies aboutPPMOs and their toxicity are still needed.

Keywords:

Duchenne Muscular Dystrophy(DMD) , Exon-skipping , Antisense OligoNucleotides(AON) , peptide-conjugated PMO(PPMO) , Phosphorodiamidate Morpholino Oligomer (PMO)