Graduate Student Seminar Series
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Presentation Title: Pulmonary Delivery of Engineered tRNA Using Lipid Nanoparticles for Overcoming Nonsense Mutations in Cystic Fibrosis
Abstract: Cystic fibrosis (CF) is a rare but debilitating genetic disease that affects more than four thousand people in Canada and over seventy thousand people worldwide1-4. The disease is caused by the mutation of the cftr gene that encodes for cystic fibrosis transmembrane conductance regulator (CFTR), which is an essential chloride ion channel found in lung tissues and the digestive tract5. Among multiple gene mutation types identified for CF, nonsense mutation is one of the significant contributors and covers about 11% of CF patients6-8. Nonsense mutations cause premature termination codons (PTCs; also known as nonsense or stop mutations) in the cftr gene and lead to lowered mRNA levels as mRNAs are degraded through the nonsense-mediated decay pathway6-8, and the resulting CFTR protein is truncated and malfunction. Current clinically used drugs/modulators for CF are significantly less effective on CF patients with nonsense mutations and cause safety concerns9,10, indicating a pressing clinical need for safe and efficient therapeutic strategies. While premature termination is the primary outcome of PTCs, the relatively rare event of translational readthrough occurs when an aminoacyl-tRNA decodes the stop codon, which can be caused due to mutations within the tRNA anticodon or through near-cognate tRNAs. Naturally, tRNAs mediate the translation of the genetic code by linking a nucleic acid adapter with amino acids, the building blocks for proteins, and pairing to the corresponding codon on the mRNA to deliver the encoded amino acid to the ribosome. Nonsense mutations can be rescued if an aminoacyl-tRNA decodes the premature stop codon in the ribosome, thereby inducing readthrough or suppression of the mutation. This has been achieved by anti-codon-engineered transfer RNAs (ACE-tRNAs), which are derived from natural tRNAs but have their anticodon altered to base-pair with stop codons11. An ACE-tRNA can be charged with the correct amino acid by components of the endogenous protein synthesis machinery (aminoacyl-tRNA synthetases) and decoding the nonsense mutation by ACE-tRNA restores the production of the full-length protein. To this end, we aim to develop lipid nanoparticles (LNPs) specifically designed and optimized for pulmonary delivery of ACE-tRNAs, thereby offering a novel and translatable therapeutic strategy for treating CF cases caused by nonsense mutations.
Supervisor Name: Dr. Bowen Li
Year of Study: 2
Program of Study: PhD
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