Gene-editing nanoparticles correct mutations in CF models

Researchers at UT Southwestern Medical Center have 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, published in the journal Science, could offer hope for people with CF and other debilitating genetic lung diseases.

As explained by UT Southwestern’s Professor Daniel Siegwart, gene editing has the potential to revolutionise medicine, but it needs to be targeted to specific organs, tissues or cell populations in order 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 lipid nanoparticles (LNPs) 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.

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 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 LNPs 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.

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 mutant genes in most cells were corrected, leading to a restoration of 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 said, 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.

“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,” Siegwart said.

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