![]() These ASO therapies have significantly impacted the clinical course of patients who lacked therapeutic options for a long time. Since the first approval of the ASO drug fomiversen―for cytomegalovirus-associated retinitis, but later withdrawn―three other gapmer ASOs and five splice-switching ASOs have been approved ( Table 1). Steric-blocking ASOs are particularly useful for modulating splicing or other post-transcriptional gene-expression steps. These ASOs are composed of uniformly modified nucleotides or a combination of modified and DNA nucleotides ( Khvorova and Watts, 2017). In contrast, steric-blocking ASOs are designed to prevent the binding of proteins or RNPs (ribonucleoprotein complexes) that are important for RNA metabolism and processing ( Crooke et al., 2021). ‘Gapmer’ ASOs are composed of a window of >5 contiguous DNA nucleotides, flanked by modified RNA-like nucleotides, and they promote RNase H-mediated cleavage of the target RNA, which becomes destabilized ( Bennett, 2019 Crooke et al., 2021). The mechanisms of ASO drugs can be categorized into targeted degradation of RNA and occupancy-mediated steric hindrance ( Fig. ASO, antisense oligonucleotide PMO, phosphorodiamidate morpholino oligomers NMD, nonsense-mediated mRNA decay uORF, upstream open reading frame pORF, primary open reading frame PAS, polyadenylation signal. Steric-blocking ASOs are uniformly modified ASOs that sterically hinder the binding of proteins or RNPs that regulate post-transcriptional RNA processing (e.g., splicing, NMD, or polyadenylation) or translation. Gapmer ASOs downregulate gene expression by inducing RNase H-mediated degradation of the target RNA. (B) General mechanisms of gene-expression modulation by ASO. The most popular and successful conjugate is the N-acetylgalactosamine (GalNAc) moiety, which binds to the asialoglycoprotein receptor and enhances delivery of ASOs to hepatocytes. Various molecules can be conjugated to the 3’ or 5’ termini of ASOs ( Winkler, 2013). PMO modification replaces the sugar with the morpholino group and the phosphate linkages with neutral phosphorodiamidate linkages. Modification of the 2’ position of the sugar (e.g., 2’-OMe, 2’-MOE, LNA, and cEt) enhances nuclease stability and increases affinity for target RNAs. Replacement of phosphate linkages with PS linkages improves nuclease resistance and improves binding to plasma proteins. ASOs can be modified at the phosphate inter-nucleotide linkage, and at the 2’ position in the sugar. Overview of ASO properties and mechanisms. Increased SMN2 exon 7 inclusion, slows or improves the disease course Increased dystrophin production in skeletal muscle Reduction of triglycerides and reduced pancreatitis In this review, we introduce ASO therapies and their mechanisms of action, describe the opportunities and challenges for ASO therapeutics for CF, and discuss the current state and prospects of ASO therapies for CF. Although Trikafta and other CFTR-modulation therapies benefit most CF patients, there is a significant unmet therapeutic need for a subset of CF patients. Mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene cause cystic fibrosis (CF). For instance, an ASO drug called nusinersen became the first approved drug for spinal muscular atrophy, improving survival and the overall disease course. Advances in medicinal chemistry and a deeper understanding of post-transcriptional mechanisms have led to the approval of several ASO drugs for diseases that had long lacked therapeutic options. ASOs can modulate the expression of a target gene by promoting mRNA degradation or changing pre-mRNA splicing, nonsense-mediated mRNA decay, or translation. Antisense oligonucleotide (ASO) technology has become an attractive therapeutic modality for various diseases, including Mendelian disorders.
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