A Novel HBV Drug for Effective Cure of Chronic Hepatitis B
Abstract
Hepatitis B and evaluation of curative hepatitis B therapies are listed in FY20 PRMRP Topic Areas and the Areas of Encouragement, respectively. This proposal aims to test a new hepatitis B virus (HBV) cure therapy and is encouraged by FY20 PRMRP. Current HBV drugs can suppress HBV reproduction, but rarely cure chronic hepatitis B (CHB). The reason for this failure is the persistence of HBV cccDNA, the template for HBV reproduction in infected hepatocytes. A global panel of 35 HBV experts published a special paper titled, “A Research Agenda for Curing Chronic Hepatitis B Virus Infection,” in which they state that “the surest way to cure HBV is to eliminate cccDNA.” This directly targeting cccDNA strategy is widely accepted in the HBV field. However, current HBV drugs can reduce intrahepatic cccDNA level by 10- to nearly 1000-fold. For instance, average cccDNA copies were reduced from 1.05 copies per cell at treatment initiation to one copy per 250 cells (0.004 copies per cell) after 48 weeks of two HBV drug combinational therapy, implying >99% of infected cells clear HBV cccDNA. Then why does cccDNA remain persistent in an infected liver? The answer is that those cells that cleared HBV cccDNA are frequently subjected to new rounds of infection by newly released virions from remaining infected cells, and new rounds of infection keep refilling cccDNA that was cleared. Thus, the cccDNA persistence results from repeated cccDNA refilling, which is mediated by repeated rounds of infections after earlier cccDNA clearance. The fundamental problem for repeated rounds of infections is insufficient anti-HBs neutralizing antibody in CHB patients, which is caused by deficiency in anti-HBs antibody-producing B cells. Taken together, (1) to effectively cure HBV infection, repeated rounds of HBV infection in the liver must be blocked; (2) to block repeated rounds of infection, a sustained high level of anti-HBs antibody must be produced; and (3) to produce sustained high level of anti-HBs, a new approach that is independent of B cells must be utilized. Thus, this project tests a new HBV cure therapy that is aimed at blocking repeated rounds of infection and a new HBV drug that uses an adeno-associated virus (AAV) vector that carries genes encoding human monoclonal anti-HBs antibody. Once this AAV vector injected into skeletal muscle cells, a sustained high level of anti-HBs antibody will be produced. The expressed sustained high level of anti-HBs antibody by those muscle cells in hepatitis B patients will block repeated rounds of infection, thus blocking cccDNA refilling after earlier cccDNA was cleared, leading to HBV cure. The proposed HBV cure therapy does not need directly targeting cccDNA as recommended in HBV field, and it represents a paradigm shift in HBV cure strategy. The specific objective is to obtain therapeutic proof that HBV cure can be established by constantly blocking repeated rounds of infection with sustained high level of anti-HBs antibody. Chimeric mice with engrafted human liver will be HBV infected. Once the liver is fully infected, the animals will be treated by injecting this AAV vector expressing anti-HBs antibody and the control group treated with the AAV vector expressing malaria antibody. All animals will be followed for 30 weeks after treatment. It is expected that HBV functional cure achieved in HBV-infected mice after a single injection of AAV vector expressing anti-HBs antibody because of blocking repeated rounds of infection, while HBV infection remains at a steady level in mice treated with AAV vector expressing malaria antibody, which cannot block HBV infection. Innovation in HBV Field: (1) A novel therapy for HBV cure that aims to block repeated rounds of infection with sustained high level of anti-HBs antibody and does not require directly targeting cccDNA as recommended. Thus, this new treatment strategy is paradigm-shifting and making HBV cure realistic. (2) A new and more effecti
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110065
Entities
People
- Yong-yuan Zhang
Organizations
- United States Army