Scientists have made gene editing much more powerful

A new and more efficient breakthrough in gene editing

Scientists at the University of Texas at Austin have developed a more precise and efficient gene-editing approach that can correct many disease-causing mutations simultaneously in mammalian cells. This technique has also successfully repaired scoliosis-related mutations in zebrafish embryos.

This new approach is powered by retrovirals, genetic elements originally found in bacteria that help them defend against viral infections. Researchers have now used sterones for the first time to correct a disease-linked mutation in vertebrates, offering new hope for developing new gene therapies for human disorders.

“A lot of current gene editing approaches are limited to one or two mutations, leaving a lot of people behind,” said Jesse Buffington, a graduate student at the University of Texas and co-author of a new 2017 paper. Natural biotechnology. “My hope and motivation is that gene editing technology will be developed that is more inclusive of people who may have unique disease-causing mutations, and that the use of steroids will be able to extend this effect to a broader group of patients.”

Buffington led the research alongside Ilya Finkelstein, a professor of molecular biological sciences at the University of Texas, with support from Retronix Bio and the Welch Foundation.

Replacing defective DNA with healthy sequences

The retrotron-based system can replace long segments of defective DNA with healthy ones. This means that a single retron “package” can correct many mutations within the same stretch of DNA, rather than targeting one specific defect at a time.

“We want to democratize gene therapy by creating off-the-shelf tools that can treat a large group of patients in a single dose,” Finkelstein said. “This would make its development more financially feasible and much simpler from a regulatory standpoint because you only need one approval from the FDA.”

While retrons have been used before in mammalian cells, previous attempts were largely ineffective, with only about 1.5% of target cells corrected. The University of Texas at Austin team’s method greatly improved this efficiency, successfully introducing intact DNA into about 30% of target cells. Researchers believe that they can raise this number as this technology develops.

Another key advantage is that the Retron system can be delivered into cells in the form of RNA surrounded by lipid nanoparticles. These nanoparticles are specifically designed to overcome delivery issues faced by many traditional gene editing systems.

Apply this technique to cystic fibrosis

The research team is now modifying its approach to treat cystic fibrosis (CF), a life-threatening disorder caused by mutations in the CFTR gene. These mutations cause thick mucus to accumulate in the lungs, leading to chronic inflammation and long-term lung damage.

The University of Texas at Austin recently received a grant from Emily’s Entourage, a nonprofit organization dedicated to finding treatments for the approximately 10% of people with cystic fibrosis who do not benefit from current treatments. Researchers began working to replace defective regions in the CFTR gene in laboratory models that mimic the symptoms of cystic fibrosis, and later in airway cells derived from patients.

“Traditional gene editing techniques work best with single mutations and are expensive to improve, so gene therapies tend to focus on the most common mutations,” Buffington said. “But there are more than a thousand mutations that can cause cystic fibrosis. It is not financially feasible for companies to develop a gene therapy for, say, three people. With our retron-based approach, we can cut out an entire defective region and replace it with a healthy region, potentially affecting a much larger portion of the cystic fibrosis population.”

A separate grant from the Cystic Fibrosis Foundation will support similar work targeting the region of the CFTR gene that includes the most common cystic fibrosis-causing mutations.

Along with Buffington and Finkelstein, the research team includes Hong-Chi Kuo, Kwang Ho, Yu-Chun Chang, Kamyab Javanmardi, Brittney Voigt, Yi-Ru Li, Mary E. Little, and Sravan K. Devanathan, Blertha Chimalchi, and Ryan S. Gray. Their work represents an important step toward more adaptable, efficient, and comprehensive gene therapies for patients with complex genetic diseases.