P.F508del editing in cells from cystic fibrosis patients

Smirnikhina, Svetlana; Kondrateva, Ekaterina; Адильгереева, Э. П.; Анучина, А.А.; Zaynitdinova, Milyausha I.; Slesarenko, Yana; Ershova, Angelina S; Ustinov, Kirill; Yasinovsky, M.; Amelina, E.; Voronina, E. S.; Yakushina, V. D.; Tabakov, Vyacheslav; Лавров, А. В.

doi:10.1371/journal.pone.0242094

Cited by 13 publications

(11 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, CF iPSC-derived lung organoids showed a poor forskolin-induced swelling, which was restored by gene editing to correct the F508del mutation to WT-CFTR [ 165 ]. These data demonstrate the applicability of this model in CF research, and that gene editing represents a very promising technology for correcting CFTR mutations [ 175 , 176 , 177 ]. Recently three different approaches were employed to correct the F508del mutation in iPSC-derived airway epithelial cells.…”

Section: Preclinical In Vitro Modelsmentioning

confidence: 72%

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

Silva¹,

Laselva

Lopes‐Pacheco

2022

JPM

View full text Add to dashboard Cite

The development of preclinical in vitro models has provided significant progress to the studies of cystic fibrosis (CF), a frequently fatal monogenic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Numerous cell lines were generated over the last 30 years and they have been instrumental not only in enhancing the understanding of CF pathological mechanisms but also in developing therapies targeting the underlying defects in CFTR mutations with further validation in patient-derived samples. Furthermore, recent advances toward precision medicine in CF have been made possible by optimizing protocols and establishing novel assays using human bronchial, nasal and rectal tissues, and by progressing from two-dimensional monocultures to more complex three-dimensional culture platforms. These models also enable to potentially predict clinical efficacy and responsiveness to CFTR modulator therapies at an individual level. In parallel, advanced systems, such as induced pluripotent stem cells and organ-on-a-chip, continue to be developed in order to more closely recapitulate human physiology for disease modeling and drug testing. In this review, we have highlighted novel and optimized cell models that are being used in CF research to develop novel CFTR-directed therapies (or alternative therapeutic interventions) and to expand the usage of existing modulator drugs to common and rare CF-causing mutations.

show abstract

Section: Preclinical In Vitro Modelsmentioning

confidence: 72%

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

Silva¹,

Laselva

Lopes‐Pacheco

2022

JPM

View full text Add to dashboard Cite

show abstract

“…Therapies using homology-directed repair (HDR) use the natural HDR process of the cell to correct the defective CFTR gene. 24 HDR involves creating a double-stranded break on 2 ends of a target site and replacing the defective gene with a homologous and endogenous wild-type sequence. 24 The most significant caveat of this method is that HDR occurs rarely, only 1 in 10 6 times, making it extremely difficult to experiment with and an ineffective treatment.…”

Section: Homology-directed Repair and Crisprmentioning

confidence: 99%

“…24 HDR involves creating a double-stranded break on 2 ends of a target site and replacing the defective gene with a homologous and endogenous wild-type sequence. 24 The most significant caveat of this method is that HDR occurs rarely, only 1 in 10 6 times, making it extremely difficult to experiment with and an ineffective treatment. 24 Difficulties in the use of the viral and nonviral delivery mechanisms spurred the development of target integration using nucleases to provide a more pointed approach in correcting the defective CFTR gene locus.…”

Section: Homology-directed Repair and Crisprmentioning

confidence: 99%

Curative Measures for Cystic Fibrosis: A Perspective on Current Stem Cell–Based, Gene, and Small Molecule Therapies

Ajilore

Yang

Kerasidis

et al. 2022

Georgetown Medical Review

View full text Add to dashboard Cite

Cystic fibrosis (CF), which is caused by a defect or deficiency in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, continues to be a life-limiting multiorgan disease with severe phenotypic manifestations in affected patients. Current approaches to CF therapy have advanced far beyond symptomatic treatment, targeting the aberrant CFTR for therapeutic results. Novel small molecule treatments, or CF modulators, were the first to significantly improve the quality of life for patients with CF. These low-molecular-weight drugs can easily traverse the cell membrane and effect transcriptive changes in cells, albeit only for those with the specific mutations addressed by the drugs. However, other stem cell–based treatments, such as mesenchymal stromal cell therapy or induced pluripotent stem cell therapy, and gene therapies, such as CRISPR/Cas9 and viral vectors, are being researched as potential mutation-independent cures. These therapies have yet to progress to clinical trials, but their efficacies in various CF models prove their promise as future treatment options and potential cures. In this review, 3 potential contemporary therapies for CF and their current statuses and trajectories as clinical tools are discussed.

show abstract

“…After several rounds of selection-marker-free selection, corrected clones were differentiated into airway cells, demonstrating functional CFTR. F508del homozygous iPSCs were also corrected using Cas9 and F508del-specific sgRNAs with ∼2.4% efficacy ( Smirnikhina et al, 2020 ). Recently, puromycin selection of TALEN-corrected iPSCs resulted in ∼10% F508del correction efficiency ( Fleischer et al, 2020 ).…”

Section: Gene Editing To Correct Mutations In Cftr : What Has Been Done?mentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

Cystic fibrosis (CF) is a severe genetic disease for which curative treatment is still lacking. Next generation biotechnologies and more efficient cell-based and in vivo disease models are accelerating the development of novel therapies for CF. Gene editing tools, like CRISPR-based systems, can be used to make targeted modifications in the genome, allowing to correct mutations directly in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. Alternatively, with these tools more relevant disease models can be generated, which in turn will be invaluable to evaluate novel gene editing-based therapies for CF. This critical review offers a comprehensive description of currently available tools for genome editing, and the cell and animal models which are available to evaluate them. Next, we will give an extensive overview of proof-of-concept applications of gene editing in the field of CF. Finally, we will touch upon the challenges that need to be addressed before these proof-of-concept studies can be translated towards a therapy for people with CF.

show abstract

P.F508del editing in cells from cystic fibrosis patients

Cited by 13 publications

References 38 publications

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

Advances in Preclinical In Vitro Models for the Translation of Precision Medicine for Cystic Fibrosis

Curative Measures for Cystic Fibrosis: A Perspective on Current Stem Cell–Based, Gene, and Small Molecule Therapies

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

Contact Info

Product

Resources

About