Epigenetic Editing Therapy Shows Promise Against Chronic Hepatitis B

A new epigenetic treatment could offer hope for people living with chronic hepatitis B, a persistent liver infection caused by the hepatitis B virus (HBV) that affects more than 250 million people worldwide. Although existing medicines can suppress HBV, they often cannot eliminate the virus from the body.

Researchers are now testing an approach that silences HBV without cutting DNA. The experimental therapy, developed by scientists at nChroma Bio in Boston, Massachusetts, and a laboratory in Milan, Italy, chemically tags the viral genome to switch off gene activity and prevent the production of new virus particles.

The treatment produced promising results in human liver cells and mice. In monkey trials, it caused minimal and temporary side effects. The study was published in Nature Biomedical Engineering on September 21.¹

The effects of a single injection were “very impressive,” said John Tavis, a molecular virologist at St. Louis University in Missouri. “This is really where we need to be in order to finally be able to deal with this HBV pandemic around the world,” he said.

The preclinical findings “confirmed the clinical progress of this approach,” said study co-author Angelo Lombardo, a molecular biologist at the San Raffaele Telethon Gene Therapy Institute in Milan. Lombardo co-founded nChroma Bio but has no formal role at the company.

nChroma Bio has begun clinical trials testing the multi-dose treatment in Hong Kong and New Zealand. The first participants received the therapy intravenously in January. Lombardo described the human trial as a “huge step” and “the realization of years of research.”

Why chronic hepatitis B is difficult to cure

HBV infection can become a lifelong challenge because the virus can remain in the body and evade the immune system. It can form free-roaming mini-chromosomes that persist inside liver cells for long periods.

These structures, known as the “viral genomic archive,” help HBV replicate when people stop taking antiviral medicines. That can cause a severe rebound of the disease. Less than 10% of people who have received treatment for HBV for at least 10 years can stop daily medication without facing this risk, said Fabien Zurim, a virologist and clinical hepatologist at the University of Lyon in France.

HBV can also integrate parts of its genome into human DNA. This can lead to the production of proteins that alter the immune response and cause molecular changes in liver cells that may contribute to cancer, Zurim said.

How the CRMA-1001 treatment works

nChroma Bio’s treatment, called CRMA-1001, contains a modified version of the CRISPR-associated Cas9 enzyme. Unlike standard Cas9, this version lacks the enzymatic activity needed to cut DNA. The therapy also includes an RNA strand that guides the enzyme to specific locations in the HBV genome.

The treatment is delivered in lipid nanoparticles. Once inside liver cells, it is designed to silence both free and integrated HBV DNA by attaching methyl groups to the viral genome. This epigenetic editing approach changes whether genes are active without breaking DNA strands.

Epigenetic editing may avoid risks linked to DNA cutting

Gene-editing therapies that break DNA strands are also being investigated for hepatitis B. However, cutting viral DNA could potentially increase the risk of cancer, particularly because HBV can integrate into the DNA of liver cells.

By chemically tagging the HBV genome instead of cutting it, CRMA-1001 is intended to shut down viral gene activity while avoiding DNA breaks. The early results in cells, mice and monkeys have encouraged researchers to continue testing the approach in people.