The scientists used gene-editing nanoparticles to correct stem cell mutations in cystic fibrosis models, achieving long-term correction.
RT’s Three Key Takeaways:
- Researchers at UT Southwestern Medical Center developed nanoparticles that successfully edited disease-causing genes in the lungs of mice with cystic fibrosis.
- The study suggests that if these findings in mice can be translated to humans, a single-dose genome-editing therapy could potentially provide long-term therapeutic benefits for people with cystic fibrosis.
- The researchers utilized a method called Selective Organ Targeting (SORT) to deliver gene-editing machinery directly to the lungs, demonstrating significant potential for treating genetic lung diseases by specifically targeting lung stem cells.
Researchers at UT Southwestern Medical Center developed nanoparticles that successfully edited the disease-causing gene in the lungs of a mouse model of cystic fibrosis (CF), swapping a mutated form with a healthy one that persisted in stem cells.
Their findings are reported in Science.
“If these findings in mice can be translated to humans, the discovery suggests that single-dose genome-editing therapy may provide years to a lifetime of therapeutic benefit in people with CF,” says study leader Daniel Siegwart, PhD, professor of Biomedical Engineering and Biochemistry and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern, in a release.
Potential for Long-Term Therapy
Gene editing—a group of technologies designed to correct disease-causing mutations in the genome—has the potential to revolutionize medicine, says Siegwart. Targeting these technologies to specific organs, tissues, or cell populations will be necessary to effectively and safely treat patients.
In 2020, the Siegwart Lab reported a new approach that it named Selective Organ Targeting, or SORT, that uses specific components in the lipid nanoparticles that encapsulate gene-editing molecules to target certain organs. Although researchers demonstrated that SORT could deliver gene-editing machinery to the lungs, it was unknown whether this strategy could successfully edit lung stem cells.
Because the lining of the lungs renews itself every few months, editing the disease-causing genes in stem cells is essential to providing a long-lasting therapy, Siegwart says in a release.
Targeting Rare CF Mutations
Such a treatment would be especially beneficial for the roughly 10% of people with CF whose disease is caused by rare mutations in a gene called cystic fibrosis transmembrane conductance regulator (CFTR) or a specific CFTR mutation type known as “nonsense” mutations, such as R553X. Their disease cannot be treated by Trikafta, a drug that’s the current gold-standard therapy for CF.
The researchers initially worked with healthy mice that were genetically manipulated so the cells that undergo gene editing would glow red. They then intravenously delivered SORT lipid nanoparticles containing gene-editing machinery aimed at the lungs.
A persistent red glow in the lungs showed that cells with edited genes remained present for at least 22 months. Further investigation showed that more than 70% of the animals’ lung stem cells had undergone gene editing.
Human Cell Experiments
In another experiment, researchers used the SORT system on lung cells isolated from people with CF that were grown at an air-liquid interface, a scenario that mimics the biology of the lung and is considered a strong predictor of therapeutic efficacy in humans. Tests showed that over 95% of CFTR DNA was corrected, restoring functional activity comparable with what can be achieved when eligible patients are treated with Trikafta.
Next, the researchers worked with mice carrying the R553X mutation. Although mouse models of CF don’t experience the respiratory symptoms characteristic of human CF, they do have distinct physiological differences compared with healthy mice. Experiments showed that gene editing was also successful in this disease model.
Taken together, Siegwart says, these findings suggest that gene editing using SORT holds promise to treat CF and possibly other genetic lung diseases long term. More research will be necessary to investigate this approach in animal models that share CF symptoms and to ensure the safety of this prospective therapy.
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