Breakthrough: Potential Cure for Hepatitis B on the Horizon

A groundbreaking collaboration between memorial Sloan Kettering Cancer Center (MSK), Weill Cornell Medicine, and The Rockefeller University has identified a potential vulnerability in the hepatitis B virus (HBV), offering a beacon of hope for millions suffering from this deadly disease. The research, published in Cell, details how CBL137, a chromatin-destabilizing molecule already in clinical trials for cancer, successfully disrupted HBV’s ability to infect human liver cells in laboratory settings.

Chronic HBV infection, an incurable disease affecting over 325 million people globally, results in nearly 1 million deaths annually. the virus is a significant cause of liver disease and hepatocellular carcinoma, accounting for approximately half of all cases of the latter. “Over 325 million people worldwide are chronically infected by hepatitis B virus … leading to almost 1 million deaths annually despite the availability of effective vaccines,” the authors wrote. This stark reality underscores the urgent need for effective treatments beyond the current standard of care, which, while able to halt viral replication, fails to entirely eradicate the virus.

The research stemmed from a chance meeting approximately six years ago between chemical biologist Yael David, PhD, at MSK, and hepatologist and virologist Robert Schwartz, MD, PhD, at Weill Cornell Medicine. On the surface, our research programs seem to have no overlap, said David. he studies hepatitis B, while my lab focuses on understanding how gene expression is regulated thru a process called epigenetics. However, I was fascinated to discover that viruses like hepatitis B hijack epigenetic mechanisms, even using human DNA-packaging proteins to regulate their activity.

The study focused on the HBV X protein (HBx), crucial for establishing a productive infection. This protein is encoded within the viral genome,presenting a “chicken-and-egg” problem: How does the virus produce enough X protein to drive viral gene expression and establish infection? questioned David. The authors further noted that HBx is absent from the virion and must be expressed de novo in freshly infected hepatocytes … Furthermore, HBx is considered an oncogene, degrading host proteins involved in DNA repair, contributing to cancer growth.

current treatments, such as long-term oral nucleos(t)ide analogs or short-term interferon-alpha injections, only halt viral replication. One of the main challenges with treating hepatitis B is that the existing treatments can stop the virus from making new copies of itself, but they don’t fully clear the virus from infected cells, allowing the virus to persist in the liver and maintain chronic infection, explained Schwartz. Even with long-term antiviral treatment, basal levels of the HBV oncogenic X protein (HBx) remain in hepatocytes to promote genomic instability and disease progression.

The researchers’ breakthrough involved creating a recombinant, chromatinized cccDNA (covalently closed circular DNA) – the HBV minichromosome – for the first time.This allowed them to study the virus’s biochemistry and the critical early stages of infection. They discovered that the formation of nucleosomes—DNA-histone complexes—is essential for the production of protein X. … we generated recombinant, chromatinized cccDNA, allowing us to characterize it’s biophysical properties and to map nucleosome positioning on the minichromosome, the scientists explained. Viviana Risca, PhD, at The Rockefeller University, whose lab studies genome architecture, contributed expertise in ensuring the accuracy of their findings.

Contrary to conventional wisdom, Risca noted that …the presence and the positioning of nucleosomes on DNA can be important in directing cellular mechanisms to transcribe some genes. We found that to be the case for the HBV gene encoding protein X — the presence of nucleosomes on the viral genome is necessary for the transcription of RNA that gives rise to functional protein X. This finding highlighted a potential therapeutic target: disrupting nucleosome formation coudl inhibit viral infection.

Testing five small-molecule compounds, the researchers found that CBL137, an anticancer drug candidate, effectively blocked protein X production at very low concentrations, impacting the virus without harming human cells. … demonstrate CBL137 as an effective inhibitor of HBV transcription and replication that may pose a potential therapeutic avenue to treat infections, the investigators stated. David expressed optimism, stating This made us very optimistic about the possibility of developing a treatment approach while preventing or limiting side effects.Moreover, if these results are confirmed through additional study, we are optimistic the approach could be used to treat chronic infections for the first time — and therefore could represent a potential cure, added Schwartz.

The next step involves testing CBL137’s safety and efficacy in animal models, a challenge due to HBV’s limited host range. The researchers emphasized the importance of the collaborative effort,combining expertise and resources from all three institutions. Nicholas Prescott, PhD, the study’s first author, concluded, This is a grate exmaple of how investment in ‘basic science’ and inquiry of essential biological questions can open the door to medical advances… Never in a million years did I expect to lead a project that identified such a strong candidate for drug growth for a global scourge like hepatitis B.

title: Groundbreaking Discovery: Could This Be the Potential Cure for Chronic Hepatitis B That Medical Science Has Been Waiting For?

editor: Are we on the brink of a long-awaited cure for Hepatitis B, once thought incurable?

Interview with Dr. Laura Hanson,Hepatologist and Virology Expert

Hepatologist Unravels Novel Approach to Combat Hepatitis B

Intriguing breakthroughs in medical research frequently enough arise from unexpected collaborations. in this case, a groundbreaking study involving the memorial Sloan Kettering Cancer Center, Weill Cornell Medicine, and The Rockefeller University has illuminated a engaging potential vulnerability in the hepatitis B virus (HBV). Stemming from a decade-long conversation, this discovery aims to disrupt and possibly cure HBV through targeted therapeutic tactics.today, we discuss this exciting progress with Dr. Laura hanson, a leading hepatologist and virology expert.

Editor: Can you explain what makes this research so remarkable in your view?

Dr. Hanson: The crux of this discovery lies in how CBL137,a chromatin-destabilizing molecule traditionally in clinical trials for cancer treatment,targets the HBV X protein—a pivotal factor for the virus’s ability to establish an active infection. Unlike existing treatments,which only halt viral replication,CBL137 goes a step further by potentially preventing the expression of a critical protein that drives HBV infection and progression.

This is groundbreaking because it addresses a persistent issue within current therapies. As you know,over 325 million people worldwide live with chronic HBV infection—a condition that frequently enough leads to severe liver disease and cancer. Existing treatments, such as nucleos(t)ide analogs and interferon-alpha, cannot completely eliminate the virus from the liver. That’s why this new approach is revolutionary and offers hope for effective management, if not a cure, for a disease with such profound global health impacts.

Editor: How does the concept of epigenetics come into play with HBV, and what implications could it have for future treatments?

Dr. Hanson: Epigenetics, the study of changes in gene expression that don’t involve alterations to the underlying DNA sequence, is at the heart of this breakthrough.The research team discovered that HBV, much like a skilled hijacker, co-opts the host’s epigenetic mechanisms to facilitate its life cycle. Specifically, the virus uses human DNA-packaging proteins to form nucleosomes on its minichromosome, essential for producing the HBx protein.

This insight has profound implications. By targeting nucleosome formation with CBL137, the researchers can potentially disrupt the virus at a fundamental level, preventing it from producing key proteins needed for its propagation. If these results translate successfully into clinical request, treatments might not just manage symptoms but actively dismantle the pathways by which the virus sustains chronic infection.

Editor: What challenges lie ahead in bringing this potential therapeutic approach to the clinic?

Dr. Hanson: Transitioning from a promising laboratory discovery to an accessible treatment involves several hurdles. Firstly, given HBV’s limited host range, finding suitable animal models for safety and efficacy testing is crucial. This step is vital to ensure that CBL137 doesn’t impose unintended harm on human cells or cause unforeseen side effects.

Secondly, the integration of multidisciplinary expertise is necesary.This study was only possible due to the collaboration of experts in chemistry, genetics, and virology—each contributing unique insights and skills. Ongoing collaborative efforts will be crucial in refining the drug, optimizing its delivery, and ensuring it can be safely administered to patients.

the translation to clinical trials will require ample investment and support from both public and private sectors. Success at this stage could not only transform the treatment landscape for HBV but also provide a template for tackling other viral infections using epigenetic targets.

Editor: What is your outlook on the impact this discovery could have on global health?

Dr. Hanson: Should this approach prove successful, the implications for global health would be immense. Hepatitis B remains a leading cause of liver disease and cancer worldwide. By offering a treatment that can potentially cure the infection, we could see dramatic reductions in these conditions’ incidence and associated health burdens.

Moreover, this could shift treatment paradigms from merely managing chronic infections to curing them, thereby improving the quality of life for millions. Besides, such innovative research could enhance our understanding of viral diseases and their interaction with human epigenetic mechanisms, opening avenues for novel therapies beyond HBV.

Editor: Could you offer some insights into how this discovery might influence future research directions?

Dr. Hanson: This research exemplifies the importance of basic science in seeding future medical advances. By deepening our understanding of viral and host epigenetic interplay, it sets the stage for further exploration into how other viruses utilize or manipulate epigenetic factors to sustain infections.

Additionally, it could inspire a broader category of targeted therapies that disrupt pathogen life cycles at the molecular level, shifting beyond current treatment methods. Such strategies might transform our approach to a variety of chronic and acute viral infections, propelling us toward more precise and effective antiviral interventions.

Editor: How can healthcare professionals and the public contribute to supporting this type of innovative research?

Dr. Hanson: For healthcare professionals, staying abreast of emerging research in virology and epigenetics can help integrate cutting-edge science into clinical practice. Encouraging patient discussions around participation in clinical trials can also be crucial in advancing these innovative treatments.

The public can support through advocacy and awareness campaigns,and perhaps most importantly,by recognizing the importance of funding for basic science research. Public support for scientific research funding ensures that institutions have the resources needed to pursue such groundbreaking investigations.

Closing Thoughts

This research not only sheds light on a novel mechanism to potentially cure Hepatitis B but also highlights the transformative power of interdisciplinary collaboration and basic science inquiry.As the scientific community eagerly anticipates further developments, the hope is that this innovative approach marks a turning point in our battle against chronic viral infections. We invite our readers to share their thoughts and stay engaged with future updates in this exciting field.

Join the discussion on social media or leave a comment below! Let’s explore how this innovation can reshape the future of global health together.