Gene-editing nanoparticles correct stem cell mutations in cystic fibrosis models

DALLAS – June 26, 2024 – 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, reported in Science, could offer hope for people with CF and other debilitating genetic lung diseases.

Daniel Siegwart, Ph.D., is Professor of Biomedical Engineering and Biochemistry and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. He holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research.

“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,” said study leader Daniel Siegwart, Ph.D., Professor of Biomedical Engineering and Biochemistry and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern.

Gene editing – a group of technologies designed to correct disease-causing mutations in the genome – has the potential to revolutionize medicine, Dr. Siegwart explained. 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 (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, Dr. Siegwart said. 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, Dr. 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.

Other UTSW researchers who contributed to this study are co-first authors Yehui Sun, M.S., graduate student researcher, and Sumanta Chatterjee, Ph.D., Instructor of Biomedical Engineering; Raksha Jain, M.D., Professor of Internal Medicine and Medical Director of the Adult Cystic Fibrosis Program; Pratima Basak, Ph.D., Lab Manager; Xu Wang, Ph.D., Senior Research Associate; postdoctoral researchers Xizhen Lian, Ph.D., Yufen Xiao, Ph.D., Yun-Chieh Sung, Ph.D., Minjeong Kim, Ph.D., and Sang M. Lee, Ph.D.; and graduate student researchers Stephen Moore, B.S., and Shiying Wu, B.S.

Dr. Siegwart holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research. Dr. Jain is a Dedman Family Scholar in Clinical Care.

This research was funded by the Cystic Fibrosis Foundation (SIEGWA18XX0, SIEGWA21XX0, HODGES19R1, and CONLON18G0), the National Institutes of Health’s National Institute of Biomedical Imaging and Bioengineering (R01 EB025192-01A1), and a Sponsored Research Agreement with ReCode Therapeutics. The UTSW Small Animal Imaging Shared Resource is supported in part by a National Cancer Institute (NCI) Cancer Center Support Grant (P30CA142543) and the Cancer Prevention and Research Institute of Texas (CPRIT) (RP210099).

Dr. Siegwart is a co-founder and member of the scientific advisory board of ReCode Therapeutics, which has licensed intellectual property from UTSW. Dr. Siegwart has financial interests in ReCode Therapeutics, Signify Bio, and Tome Biosciences. Dr. Jain previously served on the ReCode clinical advisory committee.

About UT Southwestern Medical Center

UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 21 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,100 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.