| Autor: |
Davies JC; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; U.K. Respiratory Gene Therapy Consortium, Oxford, United Kingdom., Polineni D; Division of Allergy and Pulmonary Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, Missouri., Boyd AC; U.K. Respiratory Gene Therapy Consortium, Oxford, United Kingdom.; Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, and., Donaldson S; Division of Pulmonary Diseases and Critical Care Medicine, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Gill DR; U.K. Respiratory Gene Therapy Consortium, Oxford, United Kingdom.; Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Griesenbach U; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; U.K. Respiratory Gene Therapy Consortium, Oxford, United Kingdom., Hyde SC; U.K. Respiratory Gene Therapy Consortium, Oxford, United Kingdom.; Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom., Jain R; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas., McLachlan G; U.K. Respiratory Gene Therapy Consortium, Oxford, United Kingdom.; The Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom., Mall MA; Department of Pediatric Respiratory Medicine, Immunology, and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.; German Center for Lung Research (DZL) associated partner site, Berlin, Germany; and.; German Center for Child and Adolescent Health (DZKJ) partner site, Berlin, Germany., Alton EWFW; National Heart and Lung Institute, Imperial College London, London, United Kingdom.; U.K. Respiratory Gene Therapy Consortium, Oxford, United Kingdom. |
| Abstrakt: |
Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Although CF is a multiorgan disease, the leading causes of morbidity and mortality are related to progressive lung disease. Current understanding of the effects of the broad spectrum of CFTR mutations on CFTR function has allowed for the development of CFTR modulator therapies. Despite the remarkable impact that these therapies have had, there remains a significant proportion of people with CF (estimated at 10-15% of the global CF population) who are genetically ineligible for, or intolerant of, current CFTR-targeting therapies and whose therapeutic needs remain unmet. Inhaled genetic therapies offer the prospect of addressing the unmet pulmonary treatment need in people with CF, with several approaches, including gene addition therapy (the focus of this review), RNA-based therapies, antisense oligonucleotides, and gene editing, being explored. Various nonviral and viral vectors have been investigated for CF gene addition therapy for mutation-agnostic restoration of CFTR function in the lungs. Lentiviral vectors offer the prospect of highly efficient and long-lasting gene expression, and the potential to be safely and, in contrast to other commonly used viral vectors, effectively redosed. A third-generation lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) has been developed for the treatment of CF. Promising preclinical results support the progression of this vector carrying a full-length CFTR transgene (BI 3720931) into a first-in-human clinical trial expected to begin in 2024. |
