Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation

Oren, Yifat S.; Sinai, Michal Irony-Tur; Golec, Anita; Barchad-Avitzur, O.; Mutyam, Venkateshwar; Yao, Li; Hong, Jeong S.; Ozeri-Galai, Efrat; Hatton, Aurélie; Leibson, Chen; Carmel, Liran; Reiter, Joel; Sorscher, Eric J.; Wilton, Steve D.; Kerem, Eitan; Rowe, Steven M.; Sermet‐Gaudelus, Isabelle; Kerem, Batsheva

doi:10.1016/j.jcf.2021.06.003

Cited by 40 publications

(26 citation statements)

References 50 publications

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“…A correlation was found between the amount of correctly spliced CFTR transcripts and lung function, which highlights the potential of splicing modulation as a therapeutic approach [53]. This strategy proved efficient in primary respiratory cells carrying the 3849 + 10Kb C > T variant [35]. ASOs were shown to modulate splicing in cells with various CFTR splicing mutations and to improve CFTR activity in bronchial epithelial cells [36,37].…”

Section: Rna-based Therapiesmentioning

confidence: 89%

Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators

Fajac

Sermet

2021

Cells

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Cystic fibrosis is a severe autosomal recessive disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding the CFTR protein, a chloride channel expressed in many epithelial cells. New drugs called CFTR modulators aim at restoring the CFTR protein function, and they will benefit many patients with cystic fibrosis in the near future. However, some patients bear rare mutations that are not yet eligible for CFTR modulators, although they might be amenable to these new disease-modifying drugs. Moreover, more than 10% of CFTR mutations do not produce any CFTR protein for CFTR modulators to act upon. The purpose of this review is to provide an overview of different approaches pursued to treat patients bearing mutations ineligible for CFTR modulators. One approach is to broaden the numbers of mutations eligible for CFTR modulators. This requires developing strategies to evaluate drugs in populations bearing very rare genotypes. Other approaches aiming at correcting the CFTR defect develop new mutation-specific or mutation-agnostic therapies for mutations that do not produce a CFTR protein: readthrough agents for nonsense mutations, nucleic acid-based therapies, RNA- or DNA-based, and cell-based therapies. Most of these approaches are in pre-clinical development or, for some of them, early clinical phases. Many hurdles and challenges will have to be solved before they can be safely translated to patients.

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Section: Rna-based Therapiesmentioning

confidence: 89%

Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators

Fajac

Sermet

2021

Cells

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“…The initial expansion phase was maintained for two passages. Then cells were seeded on porous filters (as described in [16] .…”

Section: Primary Human Nasal Epithelial (Hne) Cell Sampling and Culturementioning

confidence: 99%

“…The short-circuit current (Isc) was measured using a protocol detailed previously [16] except for the use of 10 μM CFTR inhibitor CFTRinh172.…”

Section: Ussing Chamber Measurementsmentioning

confidence: 99%

Antisense oligonucleotide splicing modulation as a novel Cystic Fibrosis therapeutic approach for the W1282X nonsense mutation

Oren¹,

Avizur-Barchad²,

Ozeri-Galai³

et al. 2022

Journal of Cystic Fibrosis

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Background: Antisense oligonucleotide-based drugs for splicing modulation were recently approved for various genetic diseases with unmet need. Here we aimed to generate skipping over exon 23 of the CFTR transcript, to eliminate the W1282X nonsense mutation and avoid RNA degradation induced by the nonsense mediated mRNA decay mechanism, allowing production of partially active CFTR proteins lacking exon 23.Methods: ∼80 ASOs were screened in 16HBEge W1282X cells. ASO candidates showing significant exon skipping were assessed for their W1282X allele selectivity and the increase of CFTR protein maturation and function. The effect of a highly potent ASO candidates was further analyzed in well differentiated primary human nasal epithelial cells, derived from a W1282X homozygous patient.Results: ASO screening led to identification of several ASOs that significantly decrease the level of CFTR transcripts including exon 23. These ASOs resulted in significant levels of mature CFTR protein and together with modulators restore the channel function following free uptake into these cells. Importantly, a highly potent lead ASOs, efficiently delivered by free uptake, was able to increase the level of transcripts lacking exon 23 and restore the CFTR function in cells from a W1282X homozygote patient. Conclusion:The highly efficient exon 23 skipping induced by free uptake of the lead ASO and the resulting levels of mature CFTR protein exhibiting channel function in the presence of modulators, demonstrate the ASO therapeutic potential benefit for CF patients carrying the W1282X mutation with the objective to advance the lead candidate SPL23-2 to proof-of-concept clinical study.

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“…Outcomes from these assays can be then translated to patient drug responses in the clinic [18,24]. The availability of these transplant-derived tissues is limited, and more accessible CF patient-specific tissue models for preclinical drug testing are being developed, such as the use of using nasal epithelial brushings to harvest nasal epithelial cells (NECs) for culturing [34,44,[71][72][73][74]. Patient-derived nasal epithelial cultures show promise as a surrogate for bronchial or tracheal cultures with respect to CFTR function and functional rescue with modulators [75].…”

Section: Airway Spheroids From Primary Airway Epithelial Cellsmentioning

confidence: 99%

Three-Dimensional Airway Spheroids and Organoids for Cystic Fibrosis Research

Laselva

Conese

2021

JoR

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Cystic fibrosis (CF) is an autosomal recessive multi-organ disease caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, with morbidity and mortality primacy related to the lung disease. The CFTR protein, a chloride/bicarbonate channel, is expressed at the apical side of airway epithelial cells and is mainly involved in appropriate ion and fluid transport across the epithelium. Although many animal and cellular models have been developed to study the pathophysiological consequences of the lack/dysfunction of CFTR, only the three-dimensional (3D) structures termed “spheroids” and “organoids” can enable the reconstruction of airway mucosa to model organ development, disease pathophysiology, and drug screening. Airway spheroids and organoids can be derived from different sources, including adult lungs and induced pluripotent stem cells (iPSCs), each with its advantages and limits. Here, we review the major features of airway spheroids and organoids, anticipating that their potential in the CF field has not been fully shown. Further work is mandatory to understand whether they can accomplish better outcomes than other culture conditions of airway epithelial cells for CF personalized therapies and tissue engineering aims.

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Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation

Cited by 40 publications

References 50 publications

Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators

Therapeutic Approaches for Patients with Cystic Fibrosis Not Eligible for Current CFTR Modulators

Antisense oligonucleotide splicing modulation as a novel Cystic Fibrosis therapeutic approach for the W1282X nonsense mutation

Three-Dimensional Airway Spheroids and Organoids for Cystic Fibrosis Research

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