The potential of antisense oligonucleotide therapies for inherited childhood lung diseases

Abstract

Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism.

Keywords: Antisense oligonucleotides; Childhood; Cystic fibrosis; Inherited diseases; Surfactant disorders.

Fig. 1

Milestone timeline of the development and clinical use of antisense oligonucleotides

Fig. 2

Exondys 51™ excludes dystrophin exon 51 and corrects the DMD reading frame, therefore reducing disease severity in the most common type of DMD mutation. a Normal splicing of DMD exons 49–52. b Exon 51 is deleted from the DMD transcript as the result of a mutation at affect about 13% of DMD patients. Exondys 51 alters splicing of exon 51, removing it from the DMD transcript, restoring the reading frame and reducing disease severity, reflecting a Becker MD phenotype

Fig. 3

SPINRAZA® strengthens exon 7 recognition and retention in the SMN2 mRNA transcript, reducing SMA disease severity. a Predominant splicing of SMN2 exons 6–9. b An exonic polymorphism weakens exon 7 selection in the SMN2 mRNA. SPINRAZA® strengthens exon 7 selection in the SMN2 transcript, producing a functional protein and reducing SMA disease severity

Fig. 4

Deleterious alternative splicing of CFTR exon 10 could be addressed using splice-switching AOs. a Normal splicing of exons 9–11 of CFTR. b An intronic polymorphism weakens exon 10 selection in CFTR mRNA. AO-mediated retention of CFTR exon 10 in the mature mRNA

Fig. 5

Splice mutation in ABCA3 causes partial intron 25 inclusion in the mRNA resulting in DSPM. a Normal splicing of ABCA3 exons 24–26. b Aberrant splicing of intron 25 caused by point mutation, IVS-98T, introduces a stop codon after 77 additional amino acids after exon 25, resulting in a truncated protein. AO-mediated splice correction could potentially reduce the disease severity