Innovative Gene Therapy Enhances Liver Cell Repair

A groundbreaking approach in gene therapy, known as Repair Drive, has shown significant promise in enhancing the repair of liver cells, according to research conducted by scientists at Baylor College of Medicine and Rice University. This advanced therapy aims to address the challenges associated with correcting genetic disorders affecting the liver, which is crucial for treating nearly 700 genetic conditions.

The study, published in Science Translational Medicine, highlights the potential of Repair Drive to markedly increase the number of accurately repaired liver cells while simultaneously eliminating cells with erroneous edits. This method focuses on hepatocytes, the primary cell type in the liver, utilizing mouse models to demonstrate its effectiveness.

Historically, gene editing techniques have primarily involved disrupting or inactivating genes, making precise corrections a daunting task, especially within the liver. Dr. William Lagor, a prominent researcher in this field, emphasized the inherent regenerative capacity of the liver, which is not found in many other tissues. However, a significant barrier has been the limited number of liver cells capable of undergoing homology directed repair (HDR), which is only active in about 1% of liver cells that are actively dividing.

Repair Drive seeks to overcome this issue by creating a selective advantage for the accurately repaired hepatocytes. By encouraging these healthy cells to divide and regenerate the liver, the therapy aims to replace the diseased cells.

A distinctive feature of the Repair Drive method involves the use of small interfering RNA (siRNA) to target and eliminate unhealthy liver cells. This technique temporarily inhibits a gene essential for hepatocyte survival. Next, gene editing is employed to incorporate a recoded version of this essential gene alongside a therapeutic gene, which leads to the gradual death of unedited or incorrectly edited cells. Consequently, this opens up space for the correctly repaired cells to proliferate.

The researchers reported a remarkable increase in the percentage of precisely repaired cells, achieving over 25% compared to the previously low rate of approximately 1% in liver tissues of mouse models. Dr. Lagor likened the process to weeding a garden, where unhealthy cells are removed to allow corrected cells to flourish.

This collaborative study also drew on the expertise of Dr. Gang Bao's lab at Rice University, which played a pivotal role in the sequencing and bioinformatics analysis necessary for ensuring the precision of the gene edits. Dr. Bao noted the complexities involved in targeted gene insertion, highlighting the need for sophisticated methods to detect unintended edits that might occur during the process.

The findings indicate that Repair Drive not only boosts the number of accurately repaired cells but also reduces the proportion of cells with incorrect edits. This advancement holds promise not just for individual genetic disorders but potentially for a wide spectrum of liver diseases arising from genetic mutations.

Utilizing adeno-associated viruses (AAV) for delivering CRISPR/Cas9 technology, the researchers are optimistic about the adaptability of the Repair Drive platform. They envision it could be applicable to various delivery systems and editing techniques in the future. While further research is required to transition this innovative approach from laboratory settings to clinical applications, the potential impact on treating liver diseases is significant.