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

Area of Science:

• Pulmonary Medicine
• Genetic Diseases
• Gene Therapy

Background:

• Cystic fibrosis (CF) is a genetic disorder caused by CFTR gene mutations, primarily affecting the lungs and leading to progressive lung disease.
• Current CFTR modulator therapies are effective but do not benefit all patients, leaving an unmet need for approximately 10-15% of the global CF population.
• Gene addition therapy is being explored as a mutation-agnostic approach to restore CFTR function in the lungs for individuals ineligible for or intolerant of existing treatments.

Purpose of the Study:

• To review the development and potential of inhaled genetic therapies for cystic fibrosis, with a focus on gene addition strategies.
• To highlight the investigation of various viral and nonviral vectors for delivering the CFTR transgene to lung cells.
• To discuss the specific potential of a novel lentiviral vector (rSIV.F/HN) for CF treatment.

Main Methods:

• Exploration of different gene therapy approaches including gene addition, RNA-based therapies, antisense oligonucleotides, and gene editing for CF.
• Investigation of viral vectors, particularly lentiviral vectors, for efficient and long-lasting CFTR gene expression in the lungs.
• Development and preclinical evaluation of a third-generation lentiviral vector (rSIV.F/HN) carrying a full-length CFTR transgene (BI 3720931).

Main Results:

• Lentiviral vectors demonstrate potential for efficient, long-lasting, and safely redosable gene expression for CFTR restoration.
• The rSIV.F/HN vector, pseudotyped with Sendai virus proteins, has shown promising preclinical results for CF gene addition therapy.
• The vector BI 3720931 is advancing towards a first-in-human clinical trial anticipated to commence in 2024.

Conclusions:

• Inhaled gene addition therapy using advanced lentiviral vectors represents a promising strategy to address the unmet needs in cystic fibrosis.
• The rSIV.F/HN vector system offers a potential mutation-agnostic therapeutic option for CF patients.
• Successful progression into clinical trials signifies a significant step towards a new treatment modality for cystic fibrosis lung disease.