Approximately 260 million people, more than three percent of the world’s population, are infected with the hepatitis B virus (HBV); in the long run, this often leads to complications such as cirrhosis of the liver and liver cancer. Treatment is not yet possible with the available medication. Scientists at the German Disease Research Center (DZIF) and Eppendorf University Hospital (UKE) have now studied a new combination therapy that has proved to be highly effective in their infectious model.
The new therapeutic approach is based on shutting down the viral hepatitis B genome located in the nucleus of infectious liver cells. When the liver is implanted, the viral genome is transformed inside the nucleus into a rounded DNA molecule. This deoxyribonucleic acid is a stable molecule called cvDNA closed cell DNA (cccDNA) and is a template for the extraction of new viruses.
The cccDNA represents the main reservoir of hepatitis B viruses and enables their survival in the liver. The anthropologist, Dr. Dr. Maura Dandri and her team at UKE to prevent HBV-cccDNA from producing more viruses in the animal model.
The attack point of their treatment is the viral HBx protein, which protects the cccDNA in cell nucleus from toasting by preventing host factor (SMC complex) from binding to it. The team treated the animals on the one hand with the antiviral cytokine interferon-alpha, which had already been shown to reduce viral RNA, and on the other hand suppressed the formation of the HBx protein by RNA interference, a method by which the translation from RNA to protein was inhibited. In all cases, they were able to suppress HBx production in the majority of infectious cells, thereby suppressing the cccDNA through re-exposure of the host-limiting factor.
In addition, they combined this treatment with the administration of bulevirtide, capable of inhibiting HBV into the cells and thus redefining. In this way, the effect of cccDNA inactivation could last even beyond the end of treatment. Bulevirtide, better known by the research name myrcludex, was co-developed in the DZIF and was recently approved for the European market as an active substance in the treatment of hepatitis D.
“This combination therapy was able to achieve stable closure of the cccDNA in infectious cells,” Drs. Dandri explains. She leads the “HBV Cure” project in the DZIF and the “Virushepatitis” working group in the UKE. Even though it has only been confirmed so far in a mouse model, Dr. Dandri sure about the mix.
The results show that the HBV genome can be blocked by specific combination therapies. These approaches can now be applied in clinical trials to achieve functional treatment of chronic hepatitis B. “
Prof. Dr. Maura Dandri, geologist
Source:
German Center for Disease Research
Magazine Reference:
Allweiss, L., et al. (2021) Therapeutic closure of HBV transcripts promotes replication of the SMC5 / 6 complex and disruption of the viral genome in vivo. Gut. doi.org/10.1136/gutjnl-2020-322571.