Breakthrough in Liver Disease Treatment: VEGFA mRNA-LNP Therapy

Liver diseases, whether acute or chronic, pose a significant global health challenge. The liver has the unique ability to regenerate itself after injury. However, prolonged or severe damage can compromise this regenerative capacity, leading to life-threatening conditions such as steatosis (accumulation of fat in the liver) and fibrosis (scarring of liver tissue). A recent scientific study has brought renewed hope by discovering a novel VEGFA mRNA-LNP treatment. This therapy has shown great hope in promoting liver regeneration and reversing liver damage.

Understanding VEGFA mRNA-LNP

The therapy focuses on utilising specific biological components. One of these components is VEGFA, or Vascular Endothelial Growth Factor A, a protein that plays a crucial role in stimulating the formation of blood vessels. This process, known as angiogenesis, is crucial for delivering oxygen and nutrients to various tissues, including the liver. Without adequate blood supply, tissues cannot regenerate or function optimally. The second component of the therapy is mRNA (Messenger RNA), which serves as a molecular messenger, carrying genetic instructions from DNA to the cellular machinery responsible for protein production. The mRNA in this therapy contains the instructions for producing VEGFA, ensuring the liver cells are equipped to promote blood vessel formation and tissue repair. To effectively deliver the mRNA, the therapy uses lipid nanoparticles (LNPs), small particles made of fats. These LNPs protect the fragile mRNA and aid in transporting it into the liver cells, ensuring the treatment efficiently reaches its target.

Findings from the Study

The study’s findings underscore the critical role of VEGFA in liver regeneration. In experiments using zebrafish, researchers found that liver regeneration was significantly impaired when VEGFA receptors were blocked. Contrarily, when VEGFA levels were increased, liver recovery accelerated. Experiments on mouse models further supported this observation. By delivering VEGFA through mRNA-LNP technology, scientists observed a remarkable increase in biliary epithelial cells (BECs) conversion into hepatocytes. These functional cells make up the majority of the liver.

This cellular conversion is vital in both acute and chronic liver injury models. The therapy proved effective in both contexts, significantly reducing steatosis and fibrosis. These conditions are commonly seen in liver diseases and have long been associated with a decline in liver function. The ability of VEGFA mRNA-LNP therapy to reverse these damaging effects offers a promising avenue for restoring normal liver function in patients suffering from these conditions.

Another important finding from the study involved the identification of specific cells in diseased livers, both in humans and mice, that express a receptor called KDR, which responds to VEGFA. These cells act as a reserve pool for liver regeneration. Under the right conditions, they can convert into hepatocytes, allowing the liver to recover from damage by replacing lost or impaired cells.

Potential for Liver Disease Treatment

The implications of these findings are profound. Liver diseases often have limited treatment options, particularly in the case of conditions like fibrosis, where the damage is irreversible in its later stages. VEGFA mRNA-LNP therapy offers a novel approach to treating these diseases by utilising the body's regenerative capabilities. The use of mRNA-LNP technology, which has already proven successful in developing COVID-19 vaccines, further bolsters confidence in its safety and efficacy. The ability to deliver therapeutic instructions directly to the liver cells and promote their recovery opens new doors for patients who have few options available.

Reference:

Rizvi, F., Lee, Y.-R., Diaz-Aragon, R., Bawa, P. S., So, J., Florentino, R. M., Wu, S., Sarjoo, A., Truong, E., Smith, A. R., Wang, F., Everton, E., Ostrowska, A., Jung, K., Tam, Y., Muramatsu, H., Pardi, N., Weissman, D., Soto-Gutierrez, A., Shin, D., & Gouon-Evans, V. (2023). VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. Cell Stem Cell, 30(12), 1640. https://doi.org/10.1016/j.stem.2023.10.00