Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis
Rattachement africain : gb, us, nl, be, jp. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air-liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and 'benchmarked' against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90-100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F/HN-pseudotyped lentiviral vector into a first-in-man CF trial in 2017.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis
- Date Crossref
- 16/11/2016
- Éditeur
- BMJ
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Cystic Fibrosis Trust pays non établi dans la noticeOrganisation à but non lucratif
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Lung Institute pays non établi dans la noticeÉtablissement de santé
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Imperial College London Department of Gene Therapy pays non établi dans la noticeUniversité ou école supérieure
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Wilhelmina Children's Hospital pays non établi dans la noticeÉtablissement de santé
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Edinburgh Cancer Research pays non établi dans la noticeStructure de recherche
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KU Leuven pays non établi dans la noticeUniversité ou école supérieure
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John Radcliffe Hospital NDCLS pays non établi dans la noticeÉtablissement de santé
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ID Pharma (Japan) pays non établi dans la noticeEntreprise
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Roslin Institute pays non établi dans la noticeStructure de recherche
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University of Edinburgh IGMM pays non établi dans la noticeUniversité ou école supérieure
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UK Cystic Fibrosis Gene Therapy Consortium pays non établi dans la noticeInstitution
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University Medical Centre Department of Pediatric Pulmonology pays non établi dans la noticeUniversité ou école supérieure
Cystic Fibrosis Trust, Lung Institute et Department of Gene Therapy — Imperial College London, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.