Correction to: In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study

Sermet‐Gaudelus, Isabelle; Renouil, M.; Fajac, Anne; Bidou, Laure; Parbaille, B.; Pierrot, S.; Davy, Nolwen; Reinert, P.; Lenoir, G.; Lesure, J; Rousset, Jean‐Pierre; Edelman, A.

doi:10.1186/s12916-018-1138-z

Cited by 16 publications

(19 citation statements)

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“…We found no evidence of either with our short-term topical and intradermal gentamicin at 1 and 3 months after treatment. This was expected, since our topical and intradermal doses were far less than those used in previously published clinical studies (DMD and CF) in which systemic gentamicin at 7.5-10 mg/kg exhibited no toxicity (30,31). The amounts of gentamicin administered in our current study were much lower than systemic doses of gentamicin routinely given to patients for infections, even if 100% of the topical or intradermal gentamicin had entered the subject's systemic circulation.…”

Section: Discussionmentioning

confidence: 60%

“…Gentamicin has been shown to promote PTC read-through in several genetic disorders, such as cystic fibrosis (CF), Duchenne's muscular dystrophy (DMD), hemophilia, and retinitis pigmentosa (23)(24)(25)(26)(27). Topical gentamicin applied to the nasal epithelium of CF patients restored the CF transmembrane conductance regulator, while intravenous gentamicin has also been shown to improve the prognosis of patients with CF and DMD (28)(29)(30)(31).…”

Section: Resultsmentioning

confidence: 99%

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Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

Woodley¹,

Cogan²,

Hou³

et al. 2017

Journal of Clinical Investigation

101

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BACKGROUND.Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease caused by mutations in the gene encoding type VII collagen, the major component of anchoring fibrils (AF). We previously demonstrated that gentamicin produced functional type VII collagen in RDEB cells harboring nonsense mutations. Herein, we determined whether topical or intradermal gentamicin administration induces type VII collagen and AFs in RDEB patients. METHODS.A double-blind, placebo-controlled pilot trial assessed safety and efficacy of topical and intradermal gentamicin in 5 RDEB patients with nonsense mutations. The topical arm tested 0.1% gentamicin ointment or placebo application 3 times daily at 2 open erosion sites for 2 weeks. The intradermal arm tested daily intradermal injection of gentamicin solution (8 mg) or placebo into 2 intact skin sites for 2 days in 4 of 5 patients. Primary outcomes were induction of type VII collagen and AFs at the test sites and safety assessment. A secondary outcome assessed wound closure of topically treated erosions. RESULTS.Both topical and intradermal gentamicin administration induced type VII collagen and AFs at the dermal-epidermal junction of treatment sites. Newly created type VII collagen varied from 20% to 165% of that expressed in normal human skin and persisted for 3 months. Topical gentamicin corrected dermal-epidermal separation, improved wound closure, and reduced blister formation. There were no untoward side effects from gentamicin treatments. Type VII collagen induction did not generate anti-type VII collagen autoantibodies in patients' blood or skin.CONCLUSION. Topical and intradermal gentamicin suppresses nonsense mutations and induces type VII collagen and AFs in RDEB patients. Gentamicin therapy may provide a readily available treatment for RDEB patients with nonsense mutations. TRIAL REGISTRATION. ClinicalTrials.gov NCT02698735.

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Section: Discussionmentioning

confidence: 60%

Section: Resultsmentioning

confidence: 99%

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

Woodley¹,

Cogan²,

Hou³

et al. 2017

Journal of Clinical Investigation

101

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“…119 All patients from the four week trial rolled over into an eight week extension (total 12 week trial) and the within-group improvement in FEV 1 % predicted for the treatment group remained significant relative to baseline (3%; P=0.03) but the improvement was modest when compared with placebo (3% v 1%). 120 Four cohorts of more than 1000 patients will be evaluated in the phase III VX-661 program. The study will comprise a group of patients with two copies of the F508del mutation and groups of heterozygous patients with one copy of the F508del plus a mutation on the second allele that results in: Precision medicine: evaluating individual response to CFTR modulators People with cystic fibrosis show variable responses to CFTR modulator therapy owing to undefined mechanisms.…”

Section: Gene Replacement Therapymentioning

confidence: 99%

New and emerging targeted therapies for cystic fibrosis

Quon

Rowe

2016

BMJ

119

122

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Cystic fibrosis (CF) is a monogenic autosomal recessive disorder that affects about 70,000 people worldwide. The clinical manifestations of the disease are caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The discovery of the CFTR gene in 1989 has led to a sophisticated understanding of how thousands of mutations in the CFTR gene affect the structure and function of the CFTR protein. Much progress has been made over the past decade with the development of orally bioavailable small molecule drugs that target defective CFTR proteins caused by specific mutations. Furthermore, there is considerable optimism about the prospect of gene replacement or editing therapies to correct all mutations in cystic fibrosis. The recent approvals of ivacaftor and lumacaftor represent the genesis of a new era of precision medicine in the treatment of this condition. These drugs are having a positive impact on the lives of people with cystic fibrosis and are potentially disease modifying. This review provides an update on advances in our understanding of the structure and function of the CFTR, with a focus on state of the art targeted drugs that are in development.

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“…These CFTR protein products following PTC suppression may or may not have full function based on the nature of the amino acid substitution coupled with the site of the substitution within the full‐length protein . Drugs that induce PTC read‐through and full length CFTR production have been tested in several contexts, including cell lines, primary airway cells from CF patients with PTCs, transgenic mice, and CF patients . Some provocative small clinical trials have provided evidence that certain aminoglycosides, which are known to bind to the eukaryotic ribosome complex, can improve the function of CFTR in CF patients harboring PTC variants in CFTR .…”

Section: Additional Modulator Strategiesmentioning

confidence: 99%

“…74,75 Drugs that induce PTC read-through and full length CFTR production have been tested in several contexts, including cell lines, primary airway cells from CF patients with PTCs, transgenic mice, and CF patients. [75][76][77][78][79][80] Some provocative small clinical trials have provided evidence that certain aminoglycosides, which are known to bind to the eukaryotic ribosome complex, can improve the function of CFTR in CF patients harboring PTC variants in CFTR. 72,73,77,78 Ataluren was developed through HTS, and was studied in two phase 3 randomized, double blind placebo controlled clinical trials in CF subjects with PTC-mediated CF, but ultimately this drug was insufficient to produce measurable benefit in subjects with a harboring a variety of PTCs.…”

Section: Additional Modulator Strategiesmentioning

confidence: 99%

Rapid therapeutic advances in CFTR modulator science

Clancy

2018

Pediatric Pulmonology

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Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by variants in the gene encoding the cystic fibrosis transmembrane conduction regulator (CFTR) protein. Loss of CFTR function disrupts chloride, bicarbonate and regulation of sodium transport, producing a cascade of mucus obstruction, inflammation, pulmonary infection, and ultimately damage in numerous organs. Established CF therapies treat the downstream consequences of CFTR dysfunction and have led to steady improvements in patient survival. A class of drugs termed CFTR modulators has recently entered the CF therapeutic landscape. These drugs differ fundamentally from prior therapies in that they aim to improve the function of disease‐causing CFTR variants. This review summarizes the science behind CFTR modulators, including their targets, mechanism of action, clinical benefit, and future directions in the field. CFTR modulators have dramatically changed how CF is treated, validated CFTR as a therapeutic target, and opened the door to truly personalized therapies and treatment regimens.

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Correction to: In vitro prediction of stop-codon suppression by intravenous gentamicin in patients with cystic fibrosis: a pilot study

Cited by 16 publications

References 1 publication

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

Gentamicin induces functional type VII collagen in recessive dystrophic epidermolysis bullosa patients

New and emerging targeted therapies for cystic fibrosis

Rapid therapeutic advances in CFTR modulator science

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