Gene-editing approach may one day cure chronic hepatitis B: Study
'Highly promising' strategy found to reduce virus levels in laboratory models
A gene-editing therapy designed to specifically inactivate a hidden genetic blueprint of the hepatitis B virus (HBV) — the cause of hepatitis B — was able to reduce HBV levels in cell and mouse models, a new study showed.
Although further work is needed to validate and refine this strategy, the early preclinical data suggest that this approach may one day be used to cure chronic hepatitis B, according to the researchers.
“These results are highly promising,” Patrick Arbuthnot, the study’s senior author and a professor and leader of the Antiviral Gene Therapy Research Unit (AGTRU) at the University of the Witwatersrand in South Africa, said in a university news story.
That story called hepatitis B “a major health issue in South Africa,” and noted that “current treatments require lifelong use, which is an especially heavy burden in resource-limited settings.”
This work, Arbuthnot said, “underscores the enormous potential of gene-editing technologies to confront persistent viral infections with precision and safety.”
Titled “Lipid Nanoparticle-Encapsulated TALEN-Encoding mRNA Inactivates Hepatitis B Virus Replication in Cultured Cells and Transgenic Mice,” the study was published in the journal Viruses.
The hepatitis B virus, spread by contact with contaminated bodily fluids, infects the liver, causing liver inflammation known as hepatitis. Some people who are infected with HBV, especially children, will develop a long-lasting or chronic infection, which can lead to life-threatening complications such as liver failure and cancer.
Vaccines to prevent HBV infection are available, but not everyone has access to them, and chronic HBV remains a widespread health issue. Globally, chronic hepatitis B affects more than 296 million people, “with many living in South Africa,” the story stated.
Gene-editing technology basically works like molecular scissors
During HBV infection, the virus injects its DNA into cells, where it forms cccDNA — covalently closed circular DNA. This cccDNA serves as a reservoir for producing new viral particles.
Available treatments for hepatitis B can help slow the virus’ growth, but generally cannot eliminate the cccDNA reservoir. This means the chronic infection can be managed, but not cured.
Now, Arbuthnot and colleagues at AGTRU — including Tiffany Smith, the study’s first author and a postdoctoral research fellow at the university — developed a novel treatment to eliminate the cccDNA reservoir using a gene-editing technology called transcription activator-like effector nucleases, or TALENs.
TALENs are proteins that basically act like molecular scissors. The team modified them to specifically cut the viral cccDNA while leaving the cell’s own healthy DNA untouched.
“The ability to target the [virus’] genetic blueprint directly paves the way for reduced healthcare costs and dramatically improved outcomes,” Smith said.
To deliver the therapy to liver cells, the researchers used tiny fatty vesicles called lipid nanoparticles, or LNPs, to carry messenger RNA (mRNA), an intermediate molecule derived from DNA that guides protein production. The mRNA cargo specifically contains instructions to produce the cccDNA-targeting TALENs.
The ability to target the [virus’] genetic blueprint directly paves the way for reduced healthcare costs and dramatically improved outcomes.
This type of LNP/mRNA technology is famous for being used to make certain vaccines for COVID-19, and the general idea is similar: guiding cells to produce a specific protein by delivering mRNA with instructions to produce that protein.
But whereas vaccines deliver mRNA to produce a piece of a virus that can be targeted by the immune system, the new therapy delivers mRNA with instructions to make the cccDNA-targeting TALEN proteins.
Treatment showed acceptable safety profile in hepatitis B mouse model
In a hepatitis B liver cell model, the TALEN-based treatment reduced the levels of HBsAg, a protein that helps the virus infect liver cells, by about 80% after four days, data showed.
Further tests in a mouse model of hepatitis B indicated that the gene-editing treatment reduced circulating virus particles by more than 99%; HBsAg levels were also significantly lowered.
The mouse experiments also indicated that the therapy had an acceptable safety profile, with no signs of DNA cuts outside cccDNA, liver toxicity, or major inflammatory response.
While further work is needed before this approach can be tested in people in clinical trials, these early data show “that LNP-delivered TALEN-encoding mRNA has potentially curative use for HBV therapy,” the researchers wrote. This research “supports [the strategy’s] development for therapeutic application against the virus,” the team added.
The scientists also speculated that this gene-editing approach could be combined with currently available treatments, noting a need to study potential combination therapy in the future.
About the Author
