Leave No One Behind: development of a genetic therapy for people living with Cystic Fibrosis who do not respond to available modulators

Cystic Fibrosis (CF) is a genetic disorder caused by numerous different mutations in the CFTR gene. While many individuals with CF can now be treated with modulator drug therapies targeting these mutations, there remain patients whose specific gene variants do not respond to these modulators. For these people with unresponsive mutations, this project proposes using Prime Editing (PE), a gene modification technique, to permanently correct their gene mutations. PE will be delivered using lipid nanoparticles (LNPs), which are effective in delivering mRNA for COVID-19 vaccines. The project aims to develop new LNP formulations that can either be injected or inhaled, allowing for the delivery of PE RNA components to correct the CFTR gene mutations in lung airway cells. In the lab, a cell model will be created using a common Canadian CFTR gene mutation unresponsive to available modulators. This model will serve as the first step in testing the effectiveness of the PE therapy. The team will also assess the therapy using cells from people with CF to identify optimal LNP formulations. Following this, the LNPs containing PE components will be tested intravenously or via inhalation in a mouse model with this human CFTR gene mutation. This work, led by experts in Prime Editing, CF biology, and LNP formulation, will pave the way for clinical trials, offering hope to those people with CF whose mutations currently lack effective treatments.