Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy

Schneider, Anne-Fleur E; Aartsma‐Rus, Annemieke

doi:10.1080/14712598.2021.1832462

Cited by 22 publications

(20 citation statements)

References 129 publications

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“…Using ASOs to remove exons encoding stop codons to correct the translational open reading frame has broad applications for addressing terminating mutations. ASO-mediated reading frame correction via induced skipping of symmetrical exons has shown promise in the FDA-approved ASOs targeting PTCs in Duchenne’s muscular dystrophy ( 48 ) and also in preclinical studies in mice for the treatment of diseases such as CLN3 Batten ( 49 ). A critical requirement for this approach is that the induced protein isoform must retain partial function.…”

Section: Discussionmentioning

confidence: 99%

Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis

Michaels

Peña‐Rasgado

Kotaria

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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CFTR gene mutations that result in the introduction of premature termination codons (PTCs) are common in cystic fibrosis (CF). This mutation type causes a severe form of the disease, likely because of low CFTR messenger RNA (mRNA) expression as a result of nonsense-mediated mRNA decay, as well as the production of a nonfunctional, truncated CFTR protein. Current therapeutics for CF, which target residual protein function, are less effective in patients with these types of mutations due in part to low CFTR protein levels. Splice-switching antisense oligonucleotides (ASOs), designed to induce skipping of exons in order to restore the mRNA open reading frame, have shown therapeutic promise preclinically and clinically for a number of diseases. We hypothesized that ASO-mediated skipping of CFTR exon 23 would recover CFTR activity associated with terminating mutations in the exon, including CFTR p.W1282X, the fifth most common mutation in CF. Here, we show that CFTR lacking the amino acids encoding exon 23 is partially functional and responsive to corrector and modulator drugs currently in clinical use. ASO-induced exon 23 skipping rescued CFTR expression and chloride current in primary human bronchial epithelial cells isolated from a homozygote CFTR-W1282X patient. These results support the use of ASOs in treating CF patients with CFTR class I mutations in exon 23 that result in unstable CFTR mRNA and truncations of the CFTR protein.

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Section: Discussionmentioning

confidence: 99%

Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis

Michaels

Peña‐Rasgado

Kotaria

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Using ASOs to remove exons encoding stop codons to correct the translational open reading frame has broad applications for addressing terminating mutations. ASO-mediated reading frame correction via induced skipping of symmetrical exons has shown promise in the FDAapproved ASOs targeting PTCs in Duchenne's Muscular Dystrophy (50) and also in pre-clinical studies in mice for the treatment of diseases such as CLN3 Batten (51). A critical requirement for this approach is that the induced protein isoform must retain partial function.…”

Section: Discussionmentioning

confidence: 99%

Open reading frame correction using antisense oligonucleotides for the treatment of cystic fibrosis caused by CFTR-W1282X

Michaels

Peña‐Rasgado

Kotaria

et al. 2021

Preprint

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CFTR gene mutations that result in the introduction of premature termination codons (PTCs) are common in cystic fibrosis (CF). This mutation type causes a severe form of the disease, likely because of low CFTR mRNA expression as a result of nonsense mediated mRNA decay (NMD), as well as production of a non-functional, truncated CFTR protein. Current therapeutics for CF, which target residual protein function, are less effective in patients with these types of mutations, due in part to low CFTR protein levels. Splice-switching antisense oligonucleotides (ASOs) designed to induce skipping of exons in order to restore the mRNA open reading frame have shown therapeutic promise pre-clinically and clinically for a number of diseases. We hypothesized that ASO-mediated skipping of CFTR exon 23 would recover CFTR activity associated with terminating mutations in the exon, including CFTR p.W1282X, the 5th most common mutation in CF. Here, we show that CFTR lacking the amino acids encoding exon 23 is partially functional and responsive to corrector and modulator drugs currently in clinical use. ASO-induced exon 23 skipping rescued CFTR expression and chloride current in primary human bronchial epithelial cells isolated from homozygote CFTR-W1282X patients. These results support the use of ASOs in treating CF patients with CFTR class I mutations in exon 23 that result in unstable CFTR mRNA and truncations of the CFTR protein.

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“…Conversely, PS modification causes toxicity and adverse effects due to the affinity of phosphorothioates to plasma proteins, which consequently prevent their urinary excretion and promote their retention in other organs such as the kidneys and liver [55]. One early 2'OMePS in clinical development, drisapersen (developed by Prosensa Therapeutics, GlaxoSmithKline, and Biomarin), was abandoned after several phase II and III studies, mainly due to severe adverse events, which included injection side reactions, proteinuria, and thrombocytopenia [56][57][58]; (NCT01890798; NCT01910649; NCT02636686). The FDA did not give regulatory approval, and the application to the EMA was withdrawn and the study terminated [59,60].…”

Section: Restoring Dystrophin Protein Productionmentioning

confidence: 99%

Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy

Fortunato

Rossi

Falzarano

et al. 2021

JCM

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Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy affecting ~1:5000 live male births. Following the identification of pathogenic variations in the dystrophin gene in 1986, the underlining genotype/phenotype correlations emerged and the role of the dystrophin protein was elucidated in skeletal, smooth, and cardiac muscles, as well as in the brain. When the dystrophin protein is absent or quantitatively or qualitatively modified, the muscle cannot sustain the stress of repeated contractions. Dystrophin acts as a bridging and anchoring protein between the sarcomere and the sarcolemma, and its absence or reduction leads to severe muscle damage that eventually cannot be repaired, with its ultimate substitution by connective tissue and fat. The advances of an understanding of the molecular pathways affected in DMD have led to the development of many therapeutic strategies that tackle different aspects of disease etiopathogenesis, which have recently led to the first successful approved orphan drugs for this condition. The therapeutic advances in this field have progressed exponentially, with second-generation drugs now entering in clinical trials as gene therapy, potentially providing a further effective approach to the condition.

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Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy

Cited by 22 publications

References 129 publications

Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis

Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis

Open reading frame correction using antisense oligonucleotides for the treatment of cystic fibrosis caused by CFTR-W1282X

Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy

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