This article interprets professional academic research and does not constitute medical advice. Hepatitis B is a stubborn virus that has proven extremely difficult to eliminate. Since American scientist Baruch Blumberg first identified the hepatitis B surface antigen, humanity has been battling this pathogen for a full 60 years. As of 2025, there are as many as 250 million people chronically infected with the hepatitis B virus worldwide. In China, viral hepatitis B is classified as a Class B infectious disease, with approximately 75 million carriers, and it is linked to more than 80% of primary liver cancer cases nationwide.
In fact, existing hepatitis B treatments have never truly cured the virus. Nucleoside analogs, the first-line therapy, can suppress viral replication but cannot touch the viral DNA hidden in the nucleus of liver cells. The other mainstream drug, interferon, which activates the immune system, comes with significant side effects and limited response rates. Only 3% to 5% of patients achieve a "functional cure," meaning sustained loss of the hepatitis B surface antigen without relapse after stopping medication, while the vast majority of patients require lifelong treatment.
Recently, however, the deadlock in eradicating hepatitis B has begun to shift with the arrival of a new class of therapy. On September 21, Boston-based biotechnology company nChroma Bio, in collaboration with the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) in Milan and the National Institute of Molecular Genetics (INGM), published a paper in Nature Biomedical Engineering disclosing the complete preclinical evidence for a candidate gene therapy designated CRMA-1001. CRMA-1001 is an epigenetic therapy that does not cut DNA or rewrite gene sequences; instead, it adds chemical methyl tags to "lock" the viral DNA, forcing gene expression to shut down. Animal experiments showed that after multiple doses, both key viral indicators reached zero in 90% of cases, with the effect lasting at least six months.
The Dual Forms of DNA That Make Hepatitis B a Formidable Foe
The fundamental reason the hepatitis B virus has coexisted with humans for so long is that it hides deeply and securely. After entering liver cells, the virus repairs its partially double-stranded circular DNA into covalently closed circular DNA (cccDNA) and stores it in the nucleus like an archive. This archive does not participate in cell division or actively replicate, yet it serves as the transcription template for all viral proteins and new viral particles. As long as it remains, the virus can reignite at any time. More troublesome still, fragments of viral DNA can randomly insert into host chromosomes to form integrated DNA; even if cccDNA is cleared, these inserted fragments continue to produce hepatitis B surface antigen, keeping the body's antiviral immunity in a constant state of suppression.
Previous mainstream therapies using nucleoside analogs only block the reverse transcription step of viral replication and cannot prevent transcription of these two forms of DNA. In recent years, scientists have developed small interfering RNA (siRNA) and antisense oligonucleotide (ASO) drugs, which can degrade viral RNA post-transcriptionally, but they only control the virus through continuous dosing, and stopping often leads to relapse. To address this, nChroma decided to focus on its area of expertise. The company was formed in December 2024 through the merger of Chroma Medicine, which specializes in epigenetic editing effector proteins, and Nvelop Therapeutics, which focuses on developing non-viral vector delivery systems. CRMA-1001 is nChroma's first clinical candidate, designed to test the viability of this technology combination in practice.
Before this latest study, Angelo Lombardo, a co-founder of Chroma Medicine and an epigeneticist at SR-Tiget, had already provided key evidence for bringing this class of therapy to the clinic. In 2024, his team published research in Nature demonstrating that an epigenetic editor based on the zinc finger protein pathway, a small protein that recognizes specific DNA sequences, maintained silencing effects for nearly a year after a single dose in mice.
The "Hit-and-Run" Molecular Mechanism
The core of CRMA-1001 consists of a messenger RNA (mRNA) paired with a guide RNA (gRNA), both encapsulated in lipid nanoparticles (LNPs) and delivered to the liver via intravenous injection. The mRNA is translated in liver cells into a fusion protein. Within this protein, dCas9, a modified version that has lost its cutting ability and retains only its targeting function, handles the address-finding role; the KRAB domain temporarily suppresses transcription; and the methyltransferase domain leaves persistent methyl tags on the viral DNA, shifting it into a silent state. The gRNA locks onto a highly conserved site in the hepatitis B virus genome, ensuring the entire system precisely targets the viral DNA without harming human genes.
The most ingenious aspect of this design is its "hit-and-run" approach. Within 24 hours of dosing, the fusion protein concentration peaks; within a week, the mRNA, gRNA, and protein are all cleared from the body. However, under the influence of epigenetic maintenance mechanisms, the methyl tags they leave behind continue to replicate. Long-term tracking in non-human primates showed that after a single dose, the silencing effect remained stable for over two years. Researchers also confirmed in mouse experiments that at the highest dose, 90% of hepatitis B surface antigen and hepatitis B virus DNA in the animals' blood dropped to undetectable levels, with the effect persisting without rebound for six months after dosing. When combined with the first-line drug entecavir, the two showed an additive effect in suppressing viral DNA.
On the safety front, after cynomolgus monkeys received one dose per month for three consecutive months, the only adverse reaction observed was a transient elevation in transaminase levels in the highest dose group (2 mg/kg), which returned to normal within four weeks, with no clinical symptoms or histopathological abnormalities. The drug was primarily delivered to the liver and spleen, with no components detected in the germ cells of the testes or ovaries. To further verify the therapy's precision, researchers conducted whole-transcriptome sequencing and whole-genome methylation sequencing screens on three types of primary human cells (hepatocytes, splenic endothelial cells, and adrenocortical cells) and samples from nine donors of different ethnicities and genders, using algorithms to predict potential off-target sites. The results showed that no human genes exhibited both abnormal methylation and associated expression changes. The methyl tags spread only within a very small region around the gRNA binding site, did not trigger chromosomal rearrangements, and posed no potential risk of generating new viral variants.
However, given that no non-human primate can naturally contract hepatitis B, the therapy's conversion efficiency in patients remains unclear. How long methylation silencing can persist in humans and whether it can truly achieve "one dose, lifelong effectiveness" currently has only indirect evidence from alternative targets. Questions regarding the immunogenicity of lipid nanoparticles, whether antibodies that neutralize the therapy could develop after repeated dosing, and whether long-term combination with existing nucleoside analogs will be necessary can only be answered through human clinical trial results.
In December 2025, the Phase 1/2 clinical trial for CRMA-1001 was approved in Hong Kong, China, with the first patient dosed in January 2026. The trial is currently in the dose-escalation phase, and early clinical data have not yet been disclosed. The trial subsequently received clinical approvals in New Zealand and the UK. nChroma plans to release clinical data on improvements in hepatitis B surface antigen and hepatitis B virus DNA levels throughout 2026. If the findings support a trend toward functional cure, the program would advance to larger Phase 2b/3 trials, though it will still be years before crossing the regulatory approval threshold.
Eliminating the Virus at Its Source
To date, besides nChroma, two other companies are attempting to combat hepatitis B using epigenetic editing strategies, albeit with slightly different technical approaches. Tune Therapeutics, spun out of Duke University, was the first to enter the clinic; its candidate drug TUNE-401 received clinical trial approval in New Zealand in November 2024, and data released in May 2026 showed strong antiviral activity in chronic hepatitis B patients. Tune also uses a dCas9 plus methylation module strategy but differs from nChroma in details such as gRNA targets, delivery formulations, and dosing regimens. Shanghai-based biopharmaceutical company Epigenic Therapeutics had its candidate drug EPI-003 approved for clinical entry in New Zealand in November 2024. The company's proprietary EPIREG platform utilizes both DNA methylation and histone modification to achieve gene silencing. Its accompanying LNP delivery platform, EpiTax, is touted to reach organs beyond the liver, leaving room for pipeline expansion.
In fact, in the early days of epigenetic editing research, zinc finger proteins were the common pathway. Today, however, all three companies have shifted to using CRISPR-based dCas9 systems in their commercial pipelines, primarily because zinc finger proteins require redesigning the protein structure for each DNA target, making engineering cycles long and less reusable. The dCas9 system only requires swapping a guide RNA for retargeting, giving it far superior programmability and iteration speed. This field is rapidly moving from academic validation to industrial competition, and clinical data over the next two to three years will determine which company secures the first approved epigenetic therapy.
Looking back at history, there are many infectious diseases once deemed "incurable" that eventually saw effective drugs developed. Hepatitis C, once a stubborn disease with no vaccine that could only be barely managed with interferon, became a curable condition after Gilead's sofosbuvir was introduced in 2013. Human immunodeficiency virus (HIV) was also once viewed as a death sentence, but cocktail therapy turned it into a chronic disease, and long-acting injectables further reduced the treatment burden. Spinal muscular atrophy (SMA), once the leading genetic killer of infants, now offers affected children a chance at long-term survival thanks to antisense oligonucleotides and gene replacement therapies. Our understanding of diseases and drugs continues to deepen to the most fundamental levels, and this new research represents the first time medicine has attempted to directly shut down viral gene expression without modifying the DNA sequence. If the clinical data released later this year prove sufficiently positive, hepatitis B may finally see the dawn of a cure.
References: https://www.nature.com/articles/d41586-026-02981-9 and https://www.nature.com/articles/s41551-026-01802-8
Operation/Layout: He Chenlong. Note: Cover/first image assisted by AI generation. This article is a professional interpretation of academic research and does not constitute medical advice.