Inhibitors of neuroligin-4 & Beta-1-neurexin axis for treatment of liver disorders
Hepatic fibrosis (scar tissue) is the endpoint outcome of all chronic liver diseases from any etiology, that can progress to life threatening cirrhosis and liver cancer. The major etiologic factor for chronic liver diseases nowadays is the pandemic of fatty liver affecting up to 40-50% of adult population. Advanced hepatic fibrosis and liver cancer are yet unmet need for potent therapy.
Natural Killer (NK) cells are sub-lymphocytes which recognize the activated myofibroblast cells of the scaring and kill them by a granzyme complex mechanism. This same response is also important to prevent the rise of liver cancer. However, in advanced prolonged chronic liver diseases, the function of NK cells is impaired, allowing fibrosis progression and cancer risk.
Researchers from the Hadassah Medical Center, led by Prof. Rifaat Safadi, Director of The Liver Institute, uncovered a novel immune check point inhibitor which affects the NK cell function and causes impairment and exhaustion. The neuroligin-4 and b1-neurexin axis impairs NK cell function against fibrotic tissue and cancer. In chronic prolonged disease, NK cells overexpress neuroligin-4, while fibrotic or cancer cells overexpress b1-neurexin. The neuroligin-4 impair the NK cell function, while the b1-neurexin increase cellular proliferation. A synergistic effect of each partners occurs when neuroligin-4 & b1-neurexin synapse to each other.
The researchers synthesized novel small peptides, each has a double antagonist effect for both neuroligin-4 and b1-neurexin. As a result, NK cells recover and become strong killers, while target cells (fibrosis or cancer) decrease proliferation and become sensitive for NK killing. The final outcome is a strong anti-fibrotic and anti-cancer effects.
Efficacy was shown in several in vitro and in vivo models. Mono cultures, as well as co-cultures of NK cells, fibrotic myofibroblasts and liver cancer cells responded well to the peptides. In addition, animal models of hepatic fibrosis and cancer showed an effective therapeutic outcome.
The global liver fibrosis treatment market is estimated to be valued at US$ 14.7 billion in 2022 and is expected to exhibit a CAGR of 10.8% during the forecast period (2022-2030).