Hepatitis B virus infection is one of the important causes of liver disease, chronic hepatitis B virus infection can be divided into several stages, hepatitis B virus antigens, mainly including hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antigen, as well as HBV DNA levels are different. All chronic HBV infections may be at risk of HCC, and many teams of scientific research institutions or pharmaceutical scientists around the world are studying new ways to eliminate the hepatitis B virus.
Introduction to the principle of hepatitis B reverse transcription, a kind of RNAi under study, STSG-0002 is still in Phase 1
HBV, which is a member of the hepatoviroviridae, is an envelope virus that carries about 3.2 kb of loose ring DNA (rcDNA) as its genome. HBV's genome encodes 4 main open reading frames, core, polymerase, surface, and X protein. Among them, core and polymerases play a particularly important role in hepatitis B virus DNA replication.
After the covalent closed loop DNA (cccDNA) is formed in the infected hepatocellular nucleus, the hepatitis B virus begins to replicate, using cccDNA as the replication template for transcription, producing viral mRNA of different lengths. Among them, we call it pregenomic (pg) RNA, which also plays a very important role in hepatitis B virus replication. pgRNA, which encodes viral polymerase and core proteins, when the polymerase interacts with pgRNA, the core proteins spontaneously dimerize and then multipolymerize to assemble into the capsid of the virus.
The pgRNA-polymerase riboprotein complex is packaged with the core protein to form a nucleocapsid. Inside the nucleocapsid, the polymerase reverse-transcribes pgRNA into complementary negative-stranded DNA and further synthesizes positive-stranded DNA to produce rcDNA, which is then released around the nuclear virores.
Current methods for targeting HBV are mainly interferons and NRTIs (nucleoside (acid) reverse transcriptase inhibitors). The development and design mechanism of interferon (IFN)-α is an immunomodulator and the first method used in the field of HBV globally. Approved in 1991, interferon was also an early entrant to the HBV drug market, and it has now been replaced by a polyethylene glycolated form (Peg-IFN-α), which represents a significantly longer half-life and a more durable virological response.
The main share of the HBV drug market is the nucleoside (acid) analogue (NAs), also known as NRTIs, which as mentioned earlier is actually a potent polymerase inhibitor that scientists have proven. The main mechanism of action of polymerase inhibitors is that the incorporation of copied DNA directly targets the hepatitis B virus polymerase extension process, that is, acts as a chain terminator.
With repeated testing of NRTIs, scientists have found that even if viral genome replication is inhibited by NRTIs, the impact on hepatitis B virus replication is only temporary, and once NRTIs are stopped, mRNA expression of the virus will be restored due to the presence of cccDNA, the template of hepatitis B virus replication, which will cause hepatitis B virus replication to resume again. Therefore, scientists also regard long-term inhibition of HBV replication as the main endpoint that must be achieved by new mechanism drugs, that is, the elimination of hepatitis B surface antigen as the best endpoint, and ALT, HBVDNA, including HBsAg levels, are important predictors of long-term prognosis.
Xiaofan Health Conclusion: STSG-0002 injection, is an RNAi therapeutic agent developed by China's Shutaishen (Beijing) Biopharmaceuticals, in the past progress, in the second half of 2020, it was approved by NMPA to carry out clinical trials, and completed the first case of Phase 1a administration at the end of August last year. Recently, the company's research minutes show that due to the influence of many factors, hepatitis B gene therapy STSG-0002 is still in the Phase 1 clinical trial, and there is some uncertainty in the progress of the project, but we are trying to move forward in clinical trials.