PROJECT SUMMARY
Cystic fibrosis (CF) is a debilitating genetic disorder that predominantly impacts the lungs and pancreas due to
mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Specifically, nonsense
mutations, which produce truncated, non-functional proteins, account for approximately 11% of all CF cases.
Currently, these mutations lack targeted, effective therapeutic solutions. Our research endeavors to address this
unmet clinical need by harnessing the capabilities of adenine base editors (ABEs) to correct premature
termination codons (PTCs) through translational readthrough, thereby restoring functional protein expression.
To facilitate efficient delivery, we aim to formulate lipid nanoparticles (LNPs) specifically engineered for
pulmonary ABE delivery. The project is segmented into three pivotal objectives: 1) the chemical refinement of
RNA-encoded ABEs to achieve optimal on-target gene-editing; 2) the development and fine-tuning of LNP
formulations to overcome challenges intrinsic to pulmonary delivery; and 3) comprehensive in vivo validation
using a CFTR nonsense mutation mouse model to assess both therapeutic efficacy and safety profiles. By
focusing on nanoparticle-mediated lung cell engineering, our approach lays the foundation for a groundbreaking,
non-viral base editing platform that could revolutionize treatment protocols for CF and other diseases stemming
from PTCs. Employing cutting-edge methodologies, including the optimization of mRNA sequences encoding
ABEs, gRNA design, and novel four-component combinatorial lipid chemistry, our project has the potential to
substantially advance genomic editor delivery to the pulmonary system. These innovations could reconfigure
therapeutic strategies for CF and other genetic diseases caused by nonsense mutations. The feasibility of this
high-impact work is reinforced by our lab's established expertise in these technologies, making it a viable
candidate for significantly advancing the nonviral delivery of genomic medicines and thereby enhancing the
therapeutic options for a wide array of lung diseases.
