Genetic therapies for cystic fibrosis lung disease

Hart, Stephen L.; Harrison, Patrick T.

doi:10.1016/j.coph.2017.10.006

Cited by 33 publications

(27 citation statements)

References 37 publications

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“…Tratamiento [14,15,[22][23][24] Principios Las recomendaciones se basan actualmente en el consenso de expertos [14,15] . El tratamiento es coordinado por el Centro de Fibrosis Quística (CFQ), que permite la colaboración entre gastroenterólogos, neumólogos, otorrinolaringólogos (ORL), microbiólogos, kinesiterapeutas, psicólogos y dietistas.…”

Section: Otras Manifestacionesunclassified

Mucoviscidosis: fisiopatología, genética, aspectos clínicos y terapéuticos

Noël

Sermet‐Gaudelus

2020

EMC - Pediatría

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Resumen: La mucoviscidosis es la enfermedad autosómica recesiva grave más frecuente que afecta a la población caucásica. En Francia, por ejemplo, la incidencia es de un caso por cada 4.500 nacimientos. Esta enfermedad se debe a mutaciones en el gen CFTR (cystic fibrosis transmembrane conductance regulator, regulador de conductancia transmembrana de la fibrosis quística), situado en el brazo largo del cromosoma 7, que codifica una proteína transmembrana implicada en la regulación del transporte transepitelial de iones cloruro (Cl -). En Francia, la mutación más frecuente (alrededor del 80% de los casos) es la deleción del aminoácido 508 (fenilalanina), denominada F508del. La ausencia o la disfunción de la proteína CFTR provoca un defecto en el transporte de Cly un aumento de la reabsorción de sal y agua, en particular en el epitelio bronquial, lo que conlleva una reducción del líquido de la superficie bronquial. Esta exocrinopatía generalizada conduce a la producción de «moco viscoso» (de ahí el nombre de mucoviscidosis), que obstruye varios sitios en el cuerpo, en particular el sistema respiratorio, el tracto digestivo y sus anexos (páncreas, vías biliares e hígado). La detección neonatal se ha generalizado desde 2002. La prueba del sudor es la prueba complementaria de referencia, validada por la identificación de dos mutaciones patógenas, para la confirmación del diagnóstico. El tratamiento es multidisciplinario. Se basa ante todo en la kinesiterapia respiratoria diaria y el tratamiento de las sobreinfecciones broncopulmonares, así como en las recomendaciones nutricionales con el uso de extractos pancreáticos. Es probable que el pronóstico, todavía muy desfavorable, se modifique con la llegada de terapias proteínicas o de edición de ácido ribonucleico o de gen. © 2020 Elsevier Masson SAS. Todos los derechos reservados.

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Section: Otras Manifestacionesunclassified

Mucoviscidosis: fisiopatología, genética, aspectos clínicos y terapéuticos

Noël

Sermet‐Gaudelus

2020

EMC - Pediatría

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“…Promising targets for CRISPR‐based therapy are respiratory conditions that arise due to a mutation in a single gene, such as CF. The majority of the hundreds of CF‐causing mutations cannot currently be treated with small molecule inhibitors, prompting a search for alternative treatment options . The potential for gene editing to correct CFTR dysfunction was demonstrated in a model system using epithelial organoids derived from intestinal stem cells .…”

Section: Crispr/cas Gene Therapy For Respiratory Diseasesmentioning

confidence: 99%

Applications of CRISPR systems in respiratory health: Entering a new ‘red pen’ era in genome editing

Moses

Kaur

2019

Respirology

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Respiratory diseases, such as influenza infection, acute tracheal bronchitis, pneumonia, tuberculosis, chronic obstructive pulmonary disease, asthma, lung cancer and nasopharyngeal carcinoma, continue to significantly impact human health. Diseases of the lung and respiratory tract are influenced by environmental conditions and socio-economic factors; however, many of these serious respiratory disorders are also rooted in genetic or epigenetic causes. Clustered regularly interspaced palindromic repeats (CRISPR) and CRISPRassociated (Cas) proteins, isolated from the immune system of prokaryotes, provide a tool to manipulate gene sequences and gene expression with significant implications for respiratory research. CRISPR/Cas systems allow preclinical modelling of causal factors involved in many respiratory diseases, providing new insights into their underlying mechanisms. CRISPR can also be used to screen for genes involved in respiratory processes, development and pathology, identifying novel disease drivers or drug targets. Finally, CRISPR/-Cas systems can potentially correct genetic mutations and edit epigenetic marks that contribute to respiratory disorders, providing a form of personalized medicine that could be used in conjunction with other technologies such as stem cell reprogramming and transplantation. CRISPR gene editing is a young field of research, and concerns regarding its specificity, as well as the need for efficient and safe delivery methods, need to be addressed further. However, CRISPR/Cas systems represent a significant step forward for research and therapy in respiratory health, and it is likely we will see the breakthroughs generated from this technology continue.

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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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Genetic therapies for cystic fibrosis lung disease

Cited by 33 publications

References 37 publications

Mucoviscidosis: fisiopatología, genética, aspectos clínicos y terapéuticos

Mucoviscidosis: fisiopatología, genética, aspectos clínicos y terapéuticos

Applications of CRISPR systems in respiratory health: Entering a new ‘red pen’ era in genome editing

A beginner's guide to gene editing

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