Nonalcoholic fatty liver disease (NAFLD) is a metabolic stress liver injury that is closely associated with insulin resistance and genetic predisposition, and the spectrum of disease includes:Nonalcoholic hepatic steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma (HCC).
NAFLD is the most common chronic liver disease worldwide, with a global prevalence of 6Between 3% and 45%, the prevalence rate in China is at the middle and upper level, as high as more than 25%, which has become the primary cause of abnormal liver biochemical indicators in China's first chronic liver disease and health examination.
NAFLD is not only associated with liver disease, disability and death, but is also associated with a high incidence of metabolic syndrome (METS-type diabetes mellitus (TT2DM), arteriosclerotic cardiovascular disease, and colorectal tumors. The prevalence of NAFLD in patients with obesity, hyperlipidemia and T2DM is as high as 60%, 90%, 27% 92% and 28% 70%, respectively, which seriously endangers human health.
NASH is an important member of the nonalcoholic fatty liver disease (NAFLD) spectrum, with a prevalence of approximately 2% to 3% in the population. Worryingly, with the prolongation of the disease, NASH patients will have a pathological repair response to chronic damage to the liver, which is often referred to as liver fibrosis, according to statisticsAbout 25% to 35% of patients will develop liver fibrosis, which in turn accelerates the progression of the disease to cirrhosis or liver cancer.
Liver fibrosis is a key step in the development of chronic liver disease to cirrhosis and an important link affecting the prognosis of chronic liver disease. Among them, liver tissue biopsy (referred to as liver biopsy) is the diagnosis of liver fibrosis"The gold standard", which can confirm the diagnosis and accurately measure the degree of inflammatory activity and fibrosis.
At present, the means of liver fibrosis** are limited, and there is still a lack of recognized specific and effective chemical drugs and biological agents. However, the number of patients who need liver transplantation for end-stage liver diseases such as decompensated cirrhosis and HCC caused by NASH is still increasing, and patients with NASH with liver fibrosis urgently need new ** to alleviate the current predicament.
Antisense oligonucleotide (ASO)**, as a small nucleic acid drug, is one of the most mature genes** at present. It complements the RNA of the target gene through the principle of base pairing, and plays a role by regulating the function of the target gene. The currently marketed ASO drugs have been used for spinal muscular atrophy, familial hypercholesterolemia, Duchenne muscular dystrophy and other diseases.
AZD2693 is a PNPLA3-targeted, GALac-conjugated ASO that inhibits PNPLA3 RNA and subsequent protein expression in the liver, potentially providing a novel and personalized option for patients with NASH with fibrosis.