Inhalable gene and RNA therapy for cystic fibrosis: perspectives and progress in clinical development.

Abstract

Small molecule modulators of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) play a key role in cystic fibrosis (CF) management. Around 10% of people with CF (pwCF), however, are ineligible for modulator therapy. Inhalable <i>CFTR</i> gene and RNA therapies have the potential to return normal CFTR function to the lungs and provide a viable alternative therapy for all pwCF, regardless of mutation. Since 1993, 22 clinical trials of CF gene and RNA therapies based on viral and non-viral vectors have been undertaken, along with many more pre-clinical studies. To date, however, no single system has shown sufficient efficacy to warrant translation of this technology into the market. Nevertheless, novel gene carriers for CF treatment are continuously being developed, building upon the outcomes of prior clinical trials and knowledge about how the gene and RNA vectors behave <i>in vivo</i>. Given the suboptimal efficacy observed in humans over the last three decades, this review provides an objective overview of the progress and future of the inhaled delivery technologies that have been examined to date and the observed challenges and benefits of each. This study explored several databases, including PubMed, Scopus, and Google Scholar from January to November 2025.