Researchers at UT Southwestern have engineered lipid nanoparticles to target specific organs for in vivo gene editing, demonstrating long-lasting effects in mouse lungs and potential for treating cystic fibrosis. The study, published in Science, introduces a method to modify stem cells within the body, potentially revolutionizing gene therapy for genetic disorders.
Selective Organ Targeting (SORT) Nanoparticles
Traditional lipid nanoparticles, while effective for drug delivery, tend to accumulate in the liver. To overcome this limitation, researchers developed SORT nanoparticles, which include a fifth lipid that directs the particles to specific organs. This modification alters the particle's physiochemical properties and attracts distinct plasma proteins, influencing tissue uptake.
"We knew that we needed to break the rules of traditional lipid nanoparticle formulations to target tissues other than the liver," said Daniel Siegwart, Ph.D., a professor at UT Southwestern Medical Center and senior author of the study. Using SORT, the team demonstrated the ability to target the liver, spleen, and lungs in mice.
Durable Gene Editing in Lung Stem Cells
Effective gene editing requires targeting stem and progenitor cells to ensure long-term correction. The team used a genetically engineered mouse model to track gene editing in lung tissues over 22 months. Results showed uniform red fluorescence throughout the lungs, indicating successful editing in multiple cell types. The editing was sustained for nearly two years, suggesting SORT nanoparticles can effectively edit stem and progenitor cell populations.
"When we tracked the animals over time, we found that these genome editing events were completely persistent, and almost two years later, the animals were equally edited as they were on the second day," Siegwart said.
Application to Cystic Fibrosis
The researchers applied their SORT nanoparticle technology to address cystic fibrosis, a genetic lung disease caused by mutations in a chloride pump. Approximately 90% of cystic fibrosis patients can be treated with existing therapies, but some mutations remain untreatable. The team focused on one such "undruggable" mutation, using lung SORT nanoparticles to deliver a gene editor that corrects the mutation.
In experiments with patient-derived cystic fibrosis lung cells, lung SORT corrected the faulty gene, restoring chloride pump function by more than 50%. In a mouse model with the undruggable human cystic fibrosis mutation, lung SORT achieved gene correction in nearly 50% of lung stem cells.
"Our early results suggest that this technique could someday correct dysfunctional proteins in the lungs, which would absolutely be transformative in the daily lives of cystic fibrosis patients," Siegwart noted.
Jermont Chen, Ph.D., at NIBIB, commented, "Through clever modifications of standard lipid nanoparticles, this team has laid the groundwork for an in vivo gene editing platform in the lungs, which could potentially be translated to other tissues down the line."
