Grant: Project Grant

Cystic fibrosis (CF) is a devastating genetic disorder that disproportionately affects Canadian children and young adults. With approximately 1 in 3,600 live births resulting in a CF diagnosis, the disease currently impacts over 4,300 Canadians. A significant subset of these cases are caused by nonsense mutations. These mutations introduce premature stop codons (PTCs) into the genetic code, leading to truncated, non-functional proteins that exacerbate the disease's symptoms. Traditional treatments for CF, such as CFTR modulator therapies, have shown promise but are largely ineffective for patients with nonsense mutations. These patients often have little to no CFTR protein expression, making existing treatments unsuitable for their condition. Therefore, there is an urgent need to develop targeted therapies that can address this gap in treatment options. This research project aims to fill this void by leveraging the potential of anti-codon-engineered transfer RNAs (ACE-tRNAs). These specialized tRNAs are designed to correct PTCs through a process known as translational readthrough, thereby restoring functional CFTR protein production. The project employs a multi-pronged approach that includes the combinatorial design of ACE-tRNAs, high-throughput screening of lipid nanoparticles (LNPs) for pulmonary delivery, and rigorous testing of their efficacy in both in vitro and in vivo CF models. The project is divided into three stages: 1) ACE-tRNA design optimization; 2) LNP engineering for pulmonary delivery; 3) In vivo efficacy studies. Our multidisciplinary team combines expertise in tRNA biology, LNP technology, gene delivery, and CF research. The successful completion of this research could represent a landmark advancement in genetic therapies for CF and other genetic disorders caused by nonsense mutations.