Lentiviral Gene Therapy for Cystic Fibrosis: A Promising Approach and First-in-Human Trial

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.

Keywords: CFTR; genetic therapy; integrating vectors; lentivirus; mutation-agnostic treatment.

Figure 1.

Mechanism of disease. CFTR = cystic fibrosis transmembrane conductance regulator; Cl⁻ = chloride ion; ENaC = epithelial sodium channel; HCO₃⁻ = bicarbonate ion; Na⁺ = sodium ion.

Figure 2.

CFTR mutation classes. CFTR = cystic fibrosis transmembrane conductance regulator; Cl⁻ = chloride ion; HCO₃⁻ = bicarbonate ion.

Figure 3.

Viral gene therapy for cystic fibrosis. CFTR = cystic fibrosis transmembrane conductance regulator; Cl⁻ = chloride ion; HCO₃⁻ = bicarbonate ion.

Figure 4.

Safety of lentiviral gene therapy. (A) Deletion of long terminal repeat (LTR) promoter/enhancer reduces genotoxic risks. (1) Integrated second-generation retroviral vector with intact LTRs (non–self-inactivating [non-SIN]). The promoter/enhancer element in the U3 region of the 3′ LTR (solid arrow) has the potential to activate (dotted arrow) a cellular protooncogene. (2) Deletion of the U3 element (ΔU3) to ablate the LTR-initiated genotoxic effect is a feature of all modern SIN vectors (third-generation vectors). Host genomic DNA is shown as a thin horizontal black line. (B) Waffle charts of frequency of occurrence of oncogenic events after retroviral gene therapy (each square represents an individual subject). (1) Subjects treated with early-generation gammaretroviral vectors without SIN deletions. (2) Subjects treated with elivaldogene autotemcel (eli-cel), a SIN lentiviral vector (i.e., with ΔU3 deletions in the LTRs) but whose internal transgene promoter is derived from a retroviral LTR. (3) Subjects treated with SIN lentiviral vectors lacking any LTR-derived promoter/enhancers. Eli-cell data and inferences from Jun 9–10, 2022 meeting of the U.S. Food and Drug Administration Cellular, Tissue, and Gene Therapies Advisory Committee (72); other data from Reference .