About This Project

Chronic HBV affects 296M globally, with 1.5M new cases yearly, due to the persistence of cccDNA, which is the main barrier to a cure (WHO, 2023; Revill et al., 2020). We propose a systematic review of 500+ studies to identify cccDNA vulnerabilities and rank therapies. These include CRISPR-Cas9 for DNA cleavage (Lucifora et al., 2014), RNAi for gene silencing (Guo et al., 2021), and epigenetic drugs for transcriptional silencing (Belloni et al., 2012).

Ask the Scientists

What is the context of this research?

Chronic Hepatitis B affects 296 million people and causes 820,000 deaths yearly from liver cirrhosis and cancer (WHO, 2023). The major barrier to a cure for chronic Hepatitis B Virus is cccDNA, a viral DNA form that hides in liver cells and evades current treatments. We propose the first AI-assisted systematic review of 500+ studies to uncover cccDNA’s biological vulnerabilities and rank top cure strategies: CRISPR-Cas9 (Lucifora et al., 2014), RNA interference (Guo et al., 2021), and epigenetic drugs (Belloni et al., 2012). Our goal is to publish an open-access roadmap to guide HBV cure research. Like HIV cure roadmaps (Locarnini & Hatzakis, 2015), our work will help funders and scientists focus on strategies most likely to succeed. This project is urgent. Thus, without eliminating cccDNA, millions will stay on lifelong antivirals, and 820,000 will continue to die every year. Funding this work supports a crucial first step toward curing HBV and saving lives globally.

What is the significance of this project?

Hepatitis B kills 820,000 people annually, mostly from liver failure and liver cancer (World Health Organization, 2023). Current treatments suppress HBV but can’t cure it due to covalently closed circular DNA (cccDNA), a stable viral form that persists in liver cells and drives chronic infection (Nassal, Gut, 2015). Millions remain on lifelong antivirals, which are costly and inaccessible in much of Africa and Asia (Revill et al., Lancet Gastroenterol Hepatol, 2020). Our project targets this root cause. Using AI, we will review 500+ studies to identify the best strategies to eliminate or silence cccDNA. We will publish an open-access roadmap to guide researchers and drug developers toward a cure. Just as mapping HIV’s replication cycle revolutionized treatment (Locarnini & Hatzakis, WHO Global Hepatitis Report, 2017), this work could do the same for HBV by ending lifelong therapy, preventing cancer, and saving lives globally.

What are the goals of the project?

Our goal is to eliminate Hepatitis B by targeting cccDNA, the viral reservoir that evades current therapies (WHO, 2023; CDC, 2023). Using AI, we’ll screen 500+ studies to identify host and viral factors that regulate cccDNA. Top candidates will undergo CRISPR knockout testing in HBV-infected hepatocytes (Nassal, Gut, 2015). We’ll then design gene-editing tools and screen epigenetic drugs to silence cccDNA. Promising therapies will be tested in HBV-infected humanized mice and WHV models (Revill et al., Lancet Gastroenterol Hepatol, 2020). Outcomes include cccDNA quantification, liver enzyme levels, and immune markers. Pharmacokinetics and toxicity will be evaluated to ensure safety. This work lays the foundation for IRB-approved Phase I/II human trials. With 820,000 deaths annually from HBV-related liver failure and cancer (WHO, 2023), this project could be a critical step toward a functional cure.