On the Corner of Models and Cure: Gene Editing in Cystic Fibrosis

Ensinck, Marjolein M.; Mottais, Angélique; Detry, Claire; Leal, Teresinha; Carlon, Marianne

doi:10.3389/fphar.2021.662110

Cited by 17 publications

(11 citation statements)

References 181 publications

(242 reference statements)

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“…84,85 Nevertheless, efforts are ongoing and alternative approaches including the application of alternative adeno-associated and lentiviral vectors and methods to repair defective CFTR mRNA are under investigation. 86,87 Gene editing involving CRISPR/Cas-9 technologies have potential to incorporate a functional CFTR gene into a patient's cells and hold promise for a curative therapy. 82,87 Ongoing research will undoubtedly involve exploration of how such treatments can be effectively delivered to anatomically challenging organs such as the lung and the airway epithelium.…”

Section: Genetic Therapiesmentioning

confidence: 99%

“…82,87 Ongoing research will undoubtedly involve exploration of how such treatments can be effectively delivered to anatomically challenging organs such as the lung and the airway epithelium. 85,86 Alternatively, it may be possible in the future to edit epithelial progenitor cells ex vivo and then return and engraft the corrected cells. 85 It has been recognised through the development of single-cell transcriptomics that individual subtypes of epithelial cells exist in the airway and have variable expression of CFTR.…”

Section: Genetic Therapiesmentioning

confidence: 99%

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Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis

Haq¹,

Almulhem²,

Soars³

et al. 2022

PGPM

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Cystic fibrosis (CF) is an autosomal recessive genetic condition that is caused by variants in the cystic fibrosis transmembrane conductance regulator gene. This causes multisystem disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel at the apical surface of epithelia. Until recently, treatment was directed at managing the downstream effects in affected organs, principally improving airway clearance and treating infection in the lungs and improving malabsorption in the gastrointestinal tract. Care delivered by multidisciplinary teams has yielded incremental improvements in outcomes. However, the development of small-molecule CFTR modulator drugs over the last decade has heralded a new era of CF therapeutics. Modulators target the underlying defect and improve CFTR function. Either monotherapy or a combination of modulators is used depending on the specific genotype and class of CFTR disease-causing variants that an individual has. Both ivacaftor and the ivacaftor/tezacaftor/elexacaftor combination have been demonstrated to be associated with clinically very significant benefits in randomised trials and have rapidly been made available as part of standard care in many countries. CFTR modulators represent one of the best examples of precision medicine to date. They are expensive, however, and equity of access to them worldwide remains an issue. Studies and approvals are also ongoing for children under the age of 6 years for ivacaftor/tezacaftor/elexacaftor. Furthermore, no modulators are available for around 10% of the people with CF. In this review, we firstly summarise the genetics, pathophysiology and clinical problems associated with CF. We then discuss the development of CFTR modulators and key clinical trials to support their use along with other potential future therapeutic approaches.

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Section: Genetic Therapiesmentioning

confidence: 99%

Section: Genetic Therapiesmentioning

confidence: 99%

Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis

Haq¹,

Almulhem²,

Soars³

et al. 2022

PGPM

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show abstract

“…The function of this chloride/bicarbonate channel is to regulate the exchange of electrolytes and thus the hydration levels of secretory epithelia. Loss or reduction of function in this protein leads to cycles of mucus accumulation, inflammation, and infection in the lung, progressively destroying the airway epithelium (Ensinck et al, 2021).…”

Section: Editing Outcomes Are Influenced By Tissue Architecturementioning

confidence: 99%

Tissue Specific DNA Repair Outcomes Shape the Landscape of Genome Editing

2021

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The use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 has moved from bench to bedside in less than 10years, realising the vision of correcting disease through genome editing. The accuracy and safety of this approach relies on the precise control of DNA damage and repair processes to achieve the desired editing outcomes. Strategies for modulating pathway choice for repairing CRISPR-mediated DNA double-strand breaks (DSBs) have advanced the genome editing field. However, the promise of correcting genetic diseases with CRISPR-Cas9 based therapies is restrained by a lack of insight into controlling desired editing outcomes in cells of different tissue origin. Here, we review recent developments and urge for a greater understanding of tissue specific DNA repair processes of CRISPR-induced DNA breaks. We propose that integrated mapping of tissue specific DNA repair processes will fundamentally empower the implementation of precise and safe genome editing therapies for a larger variety of diseases.

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“…Lipid-based and polymer-based nanoparticles are often used as vehicles to deliver aptamers because they can transport large payloads of charged molecules (e.g., aptamers) through the cell membrane using cell-penetrating peptides [38][39][40]. NPs can ensure a long and constant release of an aptamer to maintain a desired concentration at the target site and guarantee aptamer-protein interactions.…”

Section: Nanoparticle-mediated Deliverymentioning

confidence: 99%

Targeting SARS-CoV-2 Variants with Nucleic Acid Therapeutic Nanoparticle Conjugates

et al. 2021

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The emergence of SARS-CoV-2 variants is cause for concern, because these may become resistant to current vaccines and antiviral drugs in development. Current drugs target viral proteins, resulting in a critical need for RNA-targeted nanomedicines. To address this, a comparative analysis of SARS-CoV-2 variants was performed. Several highly conserved sites were identified, of which the most noteworthy is a partial homopurine palindrome site with >99% conservation within the coding region. This sequence was compared among recently emerged, highly infectious SARS-CoV-2 variants. Conservation of the site was maintained among these emerging variants, further contributing to its potential as a regulatory target site for SARS-CoV-2. RNAfold was used to predict the structures of the highly conserved sites, with some resulting structures being common among coronaviridae. An RNA-level regulatory map of the conserved regions of SARS-CoV-2 was produced based on the predicted structures, with each representing potential target sites for antisense oligonucleotides, triplex-forming oligomers, and aptamers. Additionally, homopurine/homopyrimidine sequences within the viral genome were identified. These sequences also demonstrate appropriate target sites for antisense oligonucleotides and triplex-forming oligonucleotides. An experimental strategy to investigate these is summarized along with potential nanoparticle types for delivery, and the advantages and disadvantages of each are discussed.

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On the Corner of Models and Cure: Gene Editing in Cystic Fibrosis

Cited by 17 publications

References 181 publications

Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis

Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis

Tissue Specific DNA Repair Outcomes Shape the Landscape of Genome Editing

Targeting SARS-CoV-2 Variants with Nucleic Acid Therapeutic Nanoparticle Conjugates

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