Correction of a Cystic Fibrosis Splicing Mutation by Antisense Oligonucleotides

Igreja, Susana; Clarke, Luka A.; Botelho, Hugo M.; Marques, Luís; Amaral, Margarida D.

doi:10.1002/humu.22931

Cited by 71 publications

(55 citation statements)

References 32 publications

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“…Eteplirsen represented an achievement in the fields of neuromuscular disease and molecular gene correction, and it was followed by the approval of nusinersen for treating spinal muscular atrophy (SMA) (23,24). Progress toward clinical development of antisense-mediated splice modulating therapy has expanded beyond the treatment of DMD to include other disorders, such as Pompe disease, cystic fibrosis, cardiomyopathies, and laminopathies (25)(26)(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers

Wyatt¹,

Demonbreun²,

Kim³

et al. 2018

JCI Insight

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Section: Introductionmentioning

confidence: 99%

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers

Wyatt¹,

Demonbreun²,

Kim³

et al. 2018

JCI Insight

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“…In addition, SSOs targeting intronic regions have lower risk of interfering with important regulatory elements than SSOs targeting exons. An SSO targeting downstream of exon 16 of the CFTR gene corrects splicing in a c.2657+5G>A mutant minigene (46), and close inspection revealed a UAG motif in the sequence blocked by the SSO. The FDA-approved SSO correcting the SMN2 exon 7 exclusion also targets the hnRNP A1 binding ISS-N1 element immediately downstream the 5′ splice site (47).…”

Section: Discussionmentioning

confidence: 99%

Blocking of an intronic splicing silencer completely rescues IKBKAP exon 20 splicing in familial dysautonomia patient cells

Bruun

Bang

Christensen

et al. 2018

Nucleic Acids Research

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Familial dysautonomia (FD) is a severe genetic disorder causing sensory and autonomic dysfunction. It is predominantly caused by a c.2204+6T>C mutation in the IKBKAP gene. This mutation decreases the 5′ splice site strength of IKBKAP exon 20 leading to exon 20 skipping and decreased amounts of full-length IKAP protein. We identified a binding site for the splicing regulatory protein hnRNP A1 downstream of the IKBKAP exon 20 5′-splice site. We show that hnRNP A1 binds to this splicing regulatory element (SRE) and that two previously described inhibitory SREs inside IKBKAP exon 20 are also bound by hnRNP A1. Knockdown of hnRNP A1 in FD patient fibroblasts increases IKBKAP exon 20 inclusion demonstrating that hnRNP A1 is a negative regulator of IKBKAP exon 20 splicing. Furthermore, by mutating the SREs in an IKBKAP minigene we show that all three SREs cause hnRNP A1-mediated exon repression. We designed splice switching oligonucleotides (SSO) that blocks the intronic hnRNP A1 binding site, and demonstrate that this completely rescues splicing of IKBKAP exon 20 in FD patient fibroblasts and increases the amounts of IKAP protein. We propose that this may be developed into a potential new specific treatment of FD.

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“…About 11% of mutations-causing CF occur by incorrect splicing and this approach has shown to modulate the splicing and restore normal full-length CFTR transcript, as well as rescue functional CFTR protein (Bonini et al, 2015; Igreja et al, 2016). …”

Section: Classes Of Cftr Mutations and Cftr Modulatorsmentioning

confidence: 99%

CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

2016

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Cystic fibrosis (CF) is the most common life-threatening monogenic disease aﬄicting Caucasian people. It affects the respiratory, gastrointestinal, glandular and reproductive systems. The major cause of morbidity and mortality in CF is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue remodeling and end-stage lung disease. Over the past decades, life expectancy of CF patients has increased due to early diagnosis and improved treatments; however, these patients still present limited quality of life. Many attempts have been made to rescue CF transmembrane conductance regulator (CFTR) expression, function and stability, thereby overcoming the molecular basis of CF. Gene and protein variances caused by CFTR mutants lead to different CF phenotypes, which then require different treatments to quell the patients’ debilitating symptoms. In order to seek better approaches to treat CF patients and maximize therapeutic effects, CFTR mutants have been stratified into six groups (although several of these mutations present pleiotropic defects). The research with CFTR modulators (read-through agents, correctors, potentiators, stabilizers and amplifiers) has achieved remarkable progress, and these drugs are translating into pharmaceuticals and personalized treatments for CF patients. This review summarizes the main molecular and clinical features of CF, emphasizes the latest clinical trials using CFTR modulators, sheds light on the molecular mechanisms underlying these new and emerging treatments, and discusses the major breakthroughs and challenges to treating all CF patients.

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Correction of a Cystic Fibrosis Splicing Mutation by Antisense Oligonucleotides

Cited by 71 publications

References 32 publications

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers

Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers

Blocking of an intronic splicing silencer completely rescues IKBKAP exon 20 splicing in familial dysautonomia patient cells

CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

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