Novel NLG4 Dependent NK Recognition: Potential Implications to the Treatment of Fibrosis in NAFLD and other disorders.
Sector: Endocrinology-Metabolic Diseases
Nonalcoholic steatohepatitis (NASH) is a leading cause of morbidity and mortality with no effective therapy. However, there are numerous NASH drugs in clinical development, with a projected market during the 2020s of >$10B. The prevalence of NASH is ~7% worldwide and growing based on increasing rates of obesity and the metabolic syndrome, and the prevalence of NASH fibrosis is >1% (>4M in US), hence there is a great medical need to treat NASH subjects with anti-fibrotic therapy. Hepatic stellate cells (HSCs) are the major cell type involved in fibrosis. Patients with advanced fibrosis need effective treatment for preventing progression of disease to cirrhosis and hepatocellular carcinoma. The anti-fibrotic activity of NK-cells is decreased in fibrosis, thus failing to prevent fibrosis associated with the progression of NASH. Targeting a molecule associated with the inhibition of NK cell anti-fibrotic activity could enable the discovery of an effective anti-fibrotic compound.
Identification of NLG4 (neuroligin-4) and its receptor as the target for treatment of NASH, liver fibrosis and cirrhosis, for a drug that would increase NK cell suppression of HSC activity in liver fibrogenesis.
Using large-scale profiling, levels of NLG4 are increased in NK in pro-fibrotic liver disease.
Increased levels of NLG4 lead to impaired NK-HSC recognition resulting in pro-fibrotic effects, while silencing of NLG4 has anti-fibrotic effects by decreasing the life span of HSCs and increasing their apoptotic killing.
NLG4-knockout mice show increased NK cell activity and minimal liver injury in a standard induced cirrhosis model in mice.
Commercial anti-NLG4 antibodies shows decreased hepatitis and decreased fibrosis markers, thus providing in-vivo proof of concept for this target.
Development of NLG4-targeted therapeutics such as antibodies or small molecules for the treatment of liver fibrosis.
A novel target for an indication with a major unmet need, which may lead to modification of the underlying fibrotic disease process. Assuming that the mechanism of action of an NGL4-targeted drug is orthogonal to that of other drugs, the new drug would be expected to be used in combination with future drugs.