With a trio of grants and a recently published review paper, Zhi Q. Yao, MD, PhD, is leading East Tennessee State University into the future of CRISPR-based gene therapy for Hepatitis B virus. Approximately 250 million people are chronically infected with hepatitis B virus (HBV) worldwide. In the United States, HBV infection remains a major public health problem. Current antiretroviral therapy using nucleotides analogs (NA) can restrict HBV replication; however, the treatment cannot eliminate the viral DNAs that are integrated into the host genome and cccDNA that is resistant to the current treatment. As such, HBV persists in NA-controlled individuals, and NA cessation readily leads to viral reactivation and disease progression. There is an urgent medical need to develop a curative strategy that can eliminate HBV (ccc)DNA without causing collateral cytotoxic effects.
Dr. Yao was most recently granted an administrative supplement for a graduate student in his lab, Addison Hill. Ms. Hill is a second-year PhD student in the Biomedical Graduate Program. The award will provide support for this trainee for four years, allowing her to complete her PhD education. Her project for this award is titled “A novel CRISPR/Cas12 system targeting HBV DNA for gene therapy.” Ms. Hill states, “The proposed project will ensure the success of my research and career goals and will allow me to gain skills and experience in gene editing research. Completion of the work outlined in this research proposal will allow me to broaden my skillset in antiviral studies under the supervision of Dr. Yao.” Dr. Yao continues, “Without advancement in new therapeutics, patients with HBV infection are subject to lifelong treatment. Thus, multimodal, robust pharmaceutical strategies are desperately needed to eliminate HBV (ccc)DNAs, which is considered the cornerstone of HBV cure. In this study, we will test the efficacy and cytotoxicity of synthetic gRNA/Cas12 RNP targeting HBV DNA using cellular HBV models. If successful, this translational research will provide a novel technology platform that may be used in combatting HBV infection, but also other emerging viral diseases. It is thus clinically significant and timely.” The multiyear supplement totals $231,315. The supplement is within the scope of its parent project, Dr. Yao's R01 award titled “Engineered exosomes carrying synthetic gRNA/Cas9 targeting HBV-infected cells” totaling $2,173,826 over five years. The goal of this study is to develop and test a novel gene therapy (engineered exosomes carrying synthetic gRNA/Cas9 RNPs) targeting HBV cccDNA in HBV-infected hepatocytes that are incurable by the current antiviral regimens, to lay the foundation for achieving the long-term goal of curing chronic HBV infection.
Dr. Yao has also been awarded a R21 grant titled, “Engineering exosomes for new gRNA/Cas therapeutics to eliminate HBV infection.” Over the course of two years, the award totals $404,207. The objective of this study is to develop a Cas12- and/or Cas13-based novel gene therapy capable of targeting HBV DNA and/or RNA. This R21 (Phase I) study may be awarded a three-year R33 (Phase II) grant if new and exciting findings are achieved during the initial two-year period. Each award is sponsored by the National Institutes of Health’s National Institute of Allergy and Infectious Diseases.
In addition, this group has published a review article in Front Genome Editing. The article, “The potential of HBV cure: an overview of CRISPR-mediated HBV gene disruption,” established their leadership in the field.
Authors of the review article are Yao, Zhi Qiang; Schank, Madison B.; Zhao, Juan; El Gazzar, Mohamed; Wang, Ling; Zhang, Yi; Hill, Addison C.; Banik, Puja; Pyburn, Jaeden S; Moorman, Jonathan P. (Authors in bold are CIIDI members or CIIDI student members)
Dr. Yao is a professor in the Department of Internal Medicine at Quillen College of Medicine. He holds the Paul Dishner Chair of Excellence in Medicine and serves as Chief of the Research Division in the Department of Internal Medicine, Director of the Center of Excellence for HIV/AIDS at Quillen College of Medicine and is the Director of the HIV and Hepatitis (HBV/HCV) Program at the James H. Quillen VA Medical Center.