HOUSTON – (Feb. 13, 2025) – The Rice University lab of bioengineer Gang Bao and collaborators at Baylor College of Medicine (BCM) have developed a new gene-editing strategy that dramatically boosts the effectiveness of gene therapies in the liver, a breakthrough that could lead to new treatments for about 700 genetic disorders in this vital organ as well as in other organs and tissues.
Gene-editing therapies are already being used to treat some rare genetic diseases, but aside from the often prohibitive costs of these therapies, the underlying mechanisms they rely on involve breaking or inactivating defective genes rather than fixing disease-causing mutations. The new method called Repair Drive makes it possible to not only repair liver cells, known as hepatocytes, at much higher rates than previously possible with conventional approaches but also equips the repaired cells with a selective advantage that allows them to outcompete incorrectly edited and unedited cells.
The findings , published in the journal Science Translational Medicine , show that Repair Drive increases the amount of correctly repaired cells from roughly 1% to more than 25% of the liver mouse models, enabling them to further divide and thus regenerate the liver.
"The liver has this inherent regenerative capacity that a lot of other tissues don't; however, one of the biggest hurdles is editing a sufficient number of cells," said William Lagor, professor of integrative physiology at BCM and a senior author on the paper. "For example, homology directed repair is the preferred pathway for fixing genes, but it is only active in the roughly 1% of liver cells that are actively dividing. This limitation has made it nearly impossible to correct genetic mutations in a significant portion of the liver. Our approach is to take that small percentage of precisely repaired cells and give them a reason to divide so that they can replace the unhealthy liver cells."
The new technique used small interfering RNA (siRNA) to temporarily inhibit an essential gene, known as FAH, that is required for the survival of hepatocytes. Next, the researchers delivered a modified version of FAH along with a therapeutic gene into a subset of cells. Because this new version of FAH was immune to the siRNA, only the gene-edited cells survived and multiplied.
"This is like giving gene-edited cells a head start in a race," said Bao, Rice's A.J. Foyt Family Professor of Bioengineering, professor of chemistry, materials science and nanoengineering and mechanical engineering, Cancer Prevention and Research Institute of Texas Scholar and a senior author on the paper. "We had to develop new methods to detect and quantify not just off-target editing but also the wide variety of gene edits at the intended target site. Many people are unaware of the complexities of performing targeted gene insertion. There are a lot of unintended edits that can occur including large deletions, large insertions and chromosomal aberrations."
Bao said he is deeply committed to collaborative work with partners in the Texas Medical Center and helps lead several key initiatives, including the Baylor/Rice Genome Editing Testing Center, which was established in 2023 with support from the National Institutes of Health's Office of Research Infrastructure Programs to provide research services to investigators across the country working on the development of new gene-editing therapies.
The Bao lab has been at the forefront of gene-editing research, focusing on improving the precision, efficiency and safety of gene-editing techniques. Bao and his team have contributed significantly to the field of CRISPR/Cas9-based gene-editing techniques, especially in the context of sickle-cell disease, a genetic disorder caused by a single-point mutation in the beta-globin gene. In this latest project involving the liver, Bao's lab carried out the next-generation sequencing and bioinformatics analysis to ensure the precision of the gene edits performed with the new Repair Drive platform.
"We're not just focusing on one disease but instead offering a solution that could be applied to a broad range of conditions caused by genetic mutations in the liver," Lagor said, while also emphasizing "the incredible interdisciplinary team that contributed to this work."
Bao praised Marco De Giorgi, assistant professor in the Lagor lab at BCM and the first author of the paper, for his "persistence and vision to overcome difficult biological and technical challenges."
"He worked very closely with associate research professor So-Hyun (Julie) Park in my group at Rice, who developed new sequencing methods that were critical to the success of the project," Bao said.
Other researchers who contributed to the findings include Adam Castoreno, Mingming Cao, Ayrea Hurley, Lavanya Saxena, Marcel A. Chuecos, Christopher J. Walkey, Alexandria M. Doerfler, Mia N. Furgurson, M. Cecilia Ljungberg, Kalyani R. Patel, Sarah Hyde, Tyler Chickering, Stephanie Lefebvre, Kelly Wassarman, Patrick Miller, June Qin, Mark K. Schlegel, Ivan Zlatev, Rich Gang Li, Jong Kim, James F. Martin, Karl-Dimiter Bissig and Vasant Jadhav. Researchers are affiliated with BCM, Rice, Alnylam Pharmaceuticals, Texas Children's Hospital, Texas Heart Institute and Duke University.
The study was supported by the U.S. National Institutes of Health (U42OD026645, DK124477, HL132840, UG3 HL151545, R01HL152314, DK115461), the American Heart Association (19POST34430092), the Texas Digestive Diseases Morphology Core (P30DK56338) and the Integrated Microscopy Core (DK56338 and CA125123) with assistance from BCM's Gene Vector Core.
