Lentiviral gene therapy for cystic fibrosis: a promising approach and first-in-human trial
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2024-12-15
Date Acceptance
2024-09-04
Citation
American Journal of Respiratory and Critical Care Medicine, 2024, 210 (12), pp.1398-1408
ISSN
1073-449X
Publisher
American Thoracic Society
Start Page
1398
End Page
1408
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Volume
210
Issue
12
Copyright Statement
© 2024 by the American Thoracic Society This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0. For commercial usage and reprints, please e-mail Diane Gern (dgern@thoracic.org).
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39236265
Subjects
CFTR
genetic therapy
integrating vectors
lentivirus
mutation-agnostic treatment
Cystic Fibrosis
Humans
Genetic Therapy
Cystic Fibrosis Transmembrane Conductance Regulator
Lentivirus
Genetic Vectors
Mutation
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2024-09-05