Genetic medicines for CF: Hype versus reality

Alton, Eric W.F.W.; Boyd, Alan; Davies, Jane C.; Gill, Deborah R.; Griesenbach, Uta; Harrison, Patrick T.; Henig, Noreen R.; Higgins, Tracy E.; Hyde, Stephen C.; Innes, J A; Korman, Michael S.D.

doi:10.1002/ppul.23543

Cited by 45 publications

(52 citation statements)

References 96 publications

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“…Since the discovery of the CFTR gene in 1989, [12][13][14] 27 clinical trials have been conducted with viral vectors or non-viral vehicles (reviewed in Sondhi et al 15 and Alton et al 16 ). The safety and tolerability of different vectors have been proven, but none have led to a persistent clinical benefit.…”

Section: Introductionmentioning

confidence: 99%

Roadmap for an early gene therapy for cystic fibrosis airway disease

2017

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Gene therapy provides a mutation-independent approach to treat or even cure CF airway disease. To develop a clinical candidate for CF gene therapy, a thorough examination of preclinical efficacy in relevant cell and animal models is a prerequisite. For a long time, the CF field was struggling with a lack of appropriate animal models for CF airway pathology. Since 2008, many different and complementary animal models have been generated that develop hallmarks of CF airway disease, including the CF pig, ferret, and rat. With this, a new era has arisen that allows investigating the efficacy of gene therapy beyond molecular and electrophysiological end-points. Successful gene therapy most likely requires an appropriate time window. CF lung pathology progresses with age and therefore an early treatment would be beneficial to prevent irreversible damage. In that regard, newborn screening programs and prenatal diagnosis already provide a basis to facilitate future preventive gene-based treatment. If successful, gene therapy for CF airway disease would markedly reduce the treatment burden and improve life quality and life expectancy of CF patients.

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Section: Introductionmentioning

confidence: 99%

Roadmap for an early gene therapy for cystic fibrosis airway disease

2017

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“…One of the major goals of our research is to apply gene editing techniques to gain a better understanding and potentially treat cystic fibrosis, which is caused by mutations in the CFTR gene (Kerem et al., ; Riordan et al., ; Rommens et al., ). To date, ZFNs, TALENs and Cas9/gRNA have all been used to edit cystic fibrosis‐causing mutations in a range of cell types using NHEJ and HDR methods (Alton et al., ; Harrison et al., ; Hart & Harrison, ; Sanz et al., ). An overview of the mechanism by which Cas9/gRNA HDR could be used to repair a stop codon mutation in the CFTR gene is shown in Figure .…”

Section: Precision Repair Of Cystic Fibrosis‐causing Mutations By Hdrmentioning

confidence: 99%

A beginner's guide to gene editing

Harrison

Hart

2018

Experimental Physiology

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Genome editing enables precise changes to be made in the genome of living cells. The technique was originally developed in the 1980s but largely limited to use in mice. The discovery that a targeted double-stranded break at a unique site in the genome, close to the site to be changed, could substantially increase the efficiency of editing raised the possibility of using the technique in a broader range of animal models and, potentially, human cells. But the challenge was to identify reagents that could create targeted breaks at a unique genomic location with minimal off-target effects. In 2005, the demonstration that programmable zinc finger nucleases (ZFNs) could perform this task led to a number of proof-of-concept studies, but a limitation was the ease with which effective ZFNs could be produced. In 2009, the development of TAL effector nucleases (TALENs) increased the specificity of gene editing and the ease of design and production. However, it was not until 2013 and the development of the clustered regularly interspaced short palindromic repeat (CRISPR) Cas9/guide RNA that gene editing became a research tool that any laboratory could use.

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“…However, we must be careful with expectations, considering what is real and what may just be fictitious (Alton et al, 2016). …”

Section: Precision Medicine – the Example Of Cystic Fibrosismentioning

confidence: 99%

Personalized or Precision Medicine? The Example of Cystic Fibrosis

Marson

2017

Front. Pharmacol.

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The advent of the knowledge on human genetics, by the identification of disease-associated variants, culminated in the understanding of human variability. With the genetic knowledge, the specificity of the clinical phenotype and the drug response of each individual were understood. Using the cystic fibrosis (CF) as an example, the new terms that emerged such as personalized medicine and precision medicine can be characterized. The genetic knowledge in CF is broad and the presence of a monogenic disease caused by mutations in the CFTR gene enables the phenotype–genotype association studies (including the response to drugs), considering the wide clinical and laboratory spectrum dependent on the mutual action of genotype, environment, and lifestyle. Regarding the CF disease, personalized medicine is the treatment directed at the symptoms, and this treatment is adjusted depending on the patient’s phenotype. However, more recently, the term precision medicine began to be widely used, although its correct application and understanding are still vague and poorly characterized. In precision medicine, we understand the individual as a response to the interrelation between environment, lifestyle, and genetic factors, which enabled the advent of new therapeutic models, such as conventional drugs adjustment by individual patient dosage and drug type and response, development of new drugs (read through, broker, enhancer, stabilizer, and amplifier compounds), genome editing by homologous recombination, zinc finger nucleases, TALEN (transcription activator-like effector nuclease), CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated endonuclease 9), and gene therapy. Thus, we introduced the terms personalized medicine and precision medicine based on the CF.

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Genetic medicines for CF: Hype versus reality

Cited by 45 publications

References 96 publications

Roadmap for an early gene therapy for cystic fibrosis airway disease

Roadmap for an early gene therapy for cystic fibrosis airway disease

A beginner's guide to gene editing

Personalized or Precision Medicine? The Example of Cystic Fibrosis

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