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Vol 56(2022) N 6 p. 816-822; DOI 10.1134/S0026893322060097 Full Text

A.P. Kostyusheva1, S.A. Brezgin1,2, N.I. Ponomareva1,2, I.A. Goptar3, A.V. Nikiforova3, V.I. Gegechkori1, V.B. Poluektova1, K.A. Turkadze1, A.E. Sudina4, V.P. Chulanov1,2,4, D.S. Kostyushev1,2*

Antiviral Activity of CRISPR/Cas9 Ribonucleoprotein Complexes on a Hepatitis B Virus Model In Vivo

1Martsinovsky Institute of Medical Parasitology, Tropical and Vector-Borne Diseases (Sechenov University), Moscow, 119048 Russia
2Sirius University of Science and Technology, Sochi, 354340 Russia
3Izmerov Research Institute of Occupational Health, Moscow, 105275 Russia
4Centre for Strategic Planning and Management of Biomedical Health Risks of the Federal Medical Biological Agency, Moscow, 119121 Russia

*dkostushev@gmail.com
Received - 2022-03-31; Revised - 2022-05-23; Accepted - 2022-05-23

Chronic hepatitis B (CHB) is caused by hepatitis B virus (HBV) infection. This disease is a key issue for global health. Modern methods of therapy do not completely eliminate HBV from infected cells and do not cure chronic infection. The CRISPR/Cas9 systems of site-specific nucleases can effectively cleave do not target DNA including viral genomes. The cleavage of the major form of the HBV genome, i.e., covalently closed circular DNA (cccDNA), leads to a robust reduction in viral replication and degradation or mutational inactivation of cccDNA. CRISPR/Cas9-based approaches are one of the most promising ways to achieve a 'sterilizing' cure of CHB, i.e., complete elimination of the virus from the body. Here, the HBV mouse model in vivo has been used to analyze the antiviral activity of the high-specific Cas9 protein and sgRNA targeting HBV genome. We have found that a single injection of short-lived ribonucleoprotein complexes of CRISPR/Cas9 results in a ~10-fold reduction in HBV DNA levels in the serum and liver of mice as early as 48 h after the start of the experiment. The remaining HBV DNAs have been found to harbor rare indel mutations. Developing new antivirals for treating CHB based on CRISPR/Cas9 ribonucleoprotein complexes could substantially reduce the duration of CHB therapy and, potentially, achieve complete elimination of viral infection.

gene editing, antiviral drugs, deletions, insertions, genome technologies, NGS



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