A supercharged oligonucleotide therapeutic has shown potential for maximizing the benefits of a genetic treatment for Duchenne muscular dystrophy (DMD) in preclinical studies.
Lead researcher Pengchao Feng, from Nanjing Antisense Biopharm, and team therefore developed a bipartite-ASO technology using a short 5’-splice site decoy (5D) sequence that promoted efficient exon skipping.
The tail is carried by the antisense part to an exon of interested by a target pre-messenger RNA.
Here, it interferes with recognition of the exon’s 5’-splice site and markedly improves exon skipping compared with ASOs without such tails.
The 5D-ASO approach was able to efficiently skip mutated exons in the DMD gene and restore dystrophin expression in the muscle tissues of a mouse model of the muscular dystrophy.
A supercharged oligonucleotide therapeutic has shown potential for maximizing the benefits of a genetic treatment for Duchenne muscular dystrophy (DMD) in preclinical studies.
The study, in PNAS, establishes the value of these bifunctional or bipartite antisense oligonucleotides (ASOs)—short, synthetic, single-stranded nucleic acid analogs comprising an antisense portion with a regulatory tail that recruits splicing suppressors—in RNA-targeted therapeutics.
DMD is an X-linked recessive progressive muscle condition that usually only affects boys and causes muscle weakness and degeneration due to mutations in a gene encoding the dystrophin protein.
Using their advanced ASO technique, the researchers were able to efficiently skip mutated exons in the DMD gene and restore dystrophin expression in muscles from mouse models of the disease.
The safety profile was deemed favorable in mouse and cynomolgus monkey models.
“These results indicate that the bipartite-ASO technology is an effective platform for exon-skipping therapeutics,” the researchers reported.
Exon-skipping ASOs have already been approved to treat DMD, but conventional designs often lack the potency needed for robust therapeutic outcomes.
Lead researcher Pengchao Feng, from Nanjing Antisense Biopharm, and team therefore developed a bipartite-ASO technology using a short 5’-splice site decoy (5D) sequence that promoted efficient exon skipping.
The simple but effective 5D-ASO technique uses a short tail sequence to enhance the splicing repression exerted by an antisense part.
The tail is carried by the antisense part to an exon of interested by a target pre-messenger RNA. Here, it interferes with recognition of the exon’s 5’-splice site and markedly improves exon skipping compared with ASOs without such tails.
The 5D-ASO approach was able to efficiently skip mutated exons in the DMD gene and restore dystrophin expression in the muscle tissues of a mouse model of the muscular dystrophy.
In particular, an 8-nt tail attached to the 5′ end of antisense sequences targeting DMD exon 51 robustly enhanced its skipping in skeletal and cardiac muscles, with efficient dystrophin restoration in genetically modified mice after systemic administration.
“We confirmed 5D-ASO’s wide applicability with diverse genes and exons,” the researchers reported.
“Moreover, using DMD exon 51 as an example, we demonstrated that this method is robustly effective in vivo.”
They added: “The lead ASO showed marked exon skipping and a favorable safety profile in cynomolgus monkeys, highlighting the approach as a powerful tool in antisense therapeutics.”
