exon 53 antisense oligonucleotide (PS/2'MOE conjugates)

exon 53 antisense oligonucleotide (PS/2'MOE conjugates) refers to a class of research-stage antisense oligonucleotides (ASOs) designed to target and skip exon 53 of the dystrophin (DMD) pre-mRNA. Developed under the UKRI-funded TransNAT consortium, these molecules feature a full phosphorothioate (PS) backbone combined with 2'-O-methoxyethyl (2'-MOE) sugar modifications. To address delivery bottlenecks such as cellular uptake, endosomal escape, and nuclear import, these ASOs are conjugated to various chemical moieties (such as lipids, vitamins, or polyamines) via different linker chemistries. Although designed to restore the reading frame of the DMD gene for the treatment of Duchenne muscular dystrophy (DMD), preclinical evaluations in human immortalized skeletal muscle cells have shown that while some conjugations improve cellular uptake, they do not necessarily enhance nuclear import or exon-skipping activity due to entrapment within endosomal and lysosomal compartments.