February 12, 2025

Precision Gene Therapy Boosts Liver Disorder Treatment

A breakthrough in gene therapy may soon offer new hope for patients suffering from genetic liver disorders. Researchers at Baylor College of Medicine and Rice University have developed a pioneering gene-editing technology called Repair Drive that significantly increases the number of correctly repaired liver cells, potentially transforming the treatment of over 700 genetic conditions related to the liver.

Precision Gene Therapy Offers New Hope for Liver Disorders

This approach may broaden the range of liver diseases that can be treated with somatic genome editing.
De Giorgi et al. (2025): In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene. Sci. Transl. Med. 17, eadk3920. DOI: 10.1126/scitranslmed.adk3920

Key Highlights

Repair Drive enhances gene-editing precision in the liver.
It increases the number of correctly repaired hepatocytes to over 25%.
The therapy eliminates incorrectly edited cells, improving treatment effectiveness.
Repair Drive holds promise for treating genetic liver diseases with minimal side effects.

For years, gene-editing technologies like CRISPR have shown promise in treating genetic diseases. However, applying these tools to the liver has been a challenge due to the low rate of gene repair in liver cells, particularly hepatocytes. The breakthrough comes with Repair Drive, a novel approach that selectively targets and enhances the division of correctly repaired cells, effectively using the liver's regenerative capacity to treat genetic disorders.

A Revolutionary Approach: The Power of Regeneration

Dr. William Lagor, senior author of the study and professor at Baylor College of Medicine, explains: "The liver has this inherent regenerative capacity that many tissues don’t, but editing a sufficient number of cells has been a major hurdle. Our method takes those small numbers of precisely repaired cells and gives them a reason to divide and replace the unhealthy cells."

The technology hinges on two key features: gene editing and selective cell elimination. By using a small interfering RNA (siRNA), Repair Drive temporarily inhibits an essential gene, fumarylacetoacetate hydrolase (Fah), causing unhealthy liver cells to die off. This process clears the way for healthy, gene-edited cells to divide and repopulate the liver. According to the researchers, this results in over a 25% increase in the number of correctly repaired cells, a significant improvement compared to the usual 1% seen with traditional methods.

Dr. Gang Bao, a collaborator on the project from Rice University, adds, "One of the most remarkable aspects of Repair Drive is that it not only enhances the number of correctly edited cells but also reduces the number of cells with incorrect edits. This precise targeting is crucial in ensuring that the therapy doesn’t introduce harmful mutations."

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. (...) 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.
Dr. William Lagor, professor of integrative physiology at Baylor and senior author on the study (source: medicalxpress)

Unleashing Potential for Genetic Liver Diseases

The potential applications for Repair Drive are vast. It could help treat a wide range of inherited liver diseases such as hereditary tyrosinemia, hemophilia, and metabolic disorders. The therapy has shown promising results in mouse models, with no signs of long-term liver toxicity or increased cancer risk, even after a year of follow-up.

"Think of a yard full of weeds—that is like a diseased liver. The weeds are cells that don't express the gene that they should be expressing (...).

Using Repair Drive, we come in and kill off the weeds, or the unhealthy cells. In doing so, we basically create space for fresh new grass plugs (i.e. corrected cells) to grow and make a new lawn.

We also spent a lot of effort making sure that the weed killing only happens for a brief period of time, and that the lawn is healthy in the long run.
Dr. William Lagor, professor of integrative physiology at Baylor and senior author on the study (source: medicalxpress)

A Step Toward Widespread Treatment of Liver Disorders

While still in its early stages, Repair Drive represents a major step toward more effective gene therapies. Unlike previous approaches that required permanent changes to essential genes, Repair Drive avoids long-term disruptions, making it safer for patients. Moreover, it could be adapted for use with various delivery systems, potentially allowing the therapy to address multiple liver diseases with a single treatment platform.

Dr. Lagor is optimistic about the future: They'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. Therefore, the flexibility of this approach is one of its most exciting aspects.

Though the therapy has shown impressive results in mice, more research and testing are needed before it can be applied in clinical settings. The team is hopeful that with further advancements, Repair Drive could eventually be used to treat patients suffering from a variety of liver conditions, potentially revolutionizing the field of gene therapy.

Future Outlook: Expanding the Horizons of Gene Therapy

In the future, the researchers envision Repair Drive being combined with other gene-editing strategies, further enhancing its effectiveness. They believe the method holds great promise not only for the liver but also for other tissues, expanding the range of genetic diseases that gene editing could address.

Repair Drive not only increased the number of precisely repaired cells, but also decreased the fraction of cells with incorrect edits. This finding is key to making gene therapy not only more efficient but also safer for long-term use.

Conclusion: A Groundbreaking Step in Gene Therapy for Liver Disorders

In conclusion, Repair Drive has the potential to offer a groundbreaking approach to gene therapy for liver disorders. By enhancing gene repair precision and allowing the liver to regenerate with healthier cells, this new technology opens up exciting possibilities for treating a wide variety of genetic liver conditions. While more research is needed to bring this therapy from the lab to clinical practice, the future of gene therapy looks brighter than ever.

Repair Drive is poised to change the landscape of liver disease treatment, providing hope for patients with genetic liver conditions and potentially reshaping the future of gene therapy as a whole.