A potential first-in-class treatment using a lentivirus-based CFTR gene addition therapy for cystic fibrosis has begun clinical trials. Boehringer Ingelheim’s gene therapy BI 3720931 delivers a full-length copy of the transmembrane conductance regulator (CFTR) gene, which in people with cystic fibrosis is mutated, into airway epithelial cells via an inhaled lentiviral vector. Mutations in the CFTR gene disrupts production of the CFTR protein, which helps regulate the amount of chloride moving in and out of cells; when absent or dysfunctional, this leads to pulmonary and pancreatic disease. Although gene therapies for cystic fibrosis have been explored since the 1990s, clinical efficacy has been low, largely because of poor gene uptake by respiratory cells, and no gene therapies are approved. Available cystic fibrosis treatments are CFTR modulator therapies designed to correct the malfunctioning protein made by the CFTR gene. BI 3720931 will be tested in people who do not respond to available chloride channel modulators, such as Vertex Pharmaceuticals’ Trikafta (elexacaftor ivacaftor tezacaftor) — around 10–15% of patients. The inhaled lentiviral vector used in BI 3720931 was developed and optimized for lungs by the UK Respiratory Gene Therapy Consortium. The group introduced viral envelope glycoproteins from murine respirovirus into the vector to aid gene transfer into airway epithelial cells. In preclinical studies, this method resulted in 9–15% of respiratory epithelial cells expressing CFTR — enough to provide likely clinical benefit — for at least 2 years. In animal models, multiple dosing was possible without interference from host immune responses. The lentiviral vector is also in preclinical testing by AlveoGene as an inhaled gene therapy for α1-antitrypsin deficiencies that affect lungs and liver.
Other early-stage trials of inhaled genetic therapies for cystic fibrosis include an adeno-associated virus-based gene therapy from 4D Molecular Therapeutics carrying a shortened version of CFTR, as well as mRNA therapies encoding full-length CFTR such as Vertex’s VX-522, ReCode Therapeutics’ RCT2100 and Arcturus Therapeutics’ ARCT-032.
