Journal
ADVANCED DRUG DELIVERY REVIEWS
Volume 168, Issue -, Pages 134-146Publisher
ELSEVIER
DOI: 10.1016/j.addr.2020.05.010
Keywords
cccDNA; ZFNs; TALENs; CRISPR/Cas; Non-viral vectors
Categories
Funding
- South African National Research Foundation (NRF) [GUN 120383, GUN 81692, GUN 68339, GUN 85981, GUN 77954]
- South African Poliomyelitis Research Foundation (PRF)
- South African Medical Research Council
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Chronic infection with hepatitis B virus remains a significant global medical issue, with the need for a cure becoming increasingly urgent as complications such as cirrhosis and hepatocellular carcinoma are often fatal. Current therapies are unable to eradicate the virus due to the persistence of viral cccDNA, making the development of methods to eliminate or inactivate the cccDNA a key focus of research in the quest to cure chronic hepatitis B.
Chronic infection with the hepatitis B virus (HBV) remains a significant worldwide medical problem. While diseases caused by HIV infection, tuberculosis and malaria are on the decline, new cases of chronic hepatitis B are on the rise. Because often fatal complications of cirrhosis and hepatocellular carcinoma are associated with chronic hepatitis B, the need for a cure is as urgent as ever. Currently licensed therapeutics fail to eradicate the virus and this is attributable to persistence of the viral replication intermediate comprising covalently closed circular DNA (cccDNA). Elimination or inactivation of the viral cccDNA is thus a goal of research aimed at hepatitis B cure. The ability to engineer nucleases that are capable of specific cleavage of a DNA sequence now provides the means to disable cccDNA permanently. The scientific literature is replete with many examples of using designer zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and RNA-guided endonucleases (RGENs) to inactivate HBV. However, important concerns about safety, dose control and efficient delivery need to be addressed before the technology is employed in a clinical setting. Use of in vitro transcribed mRNA to express therapeutic gene editors goes some way to overcoming these concerns. The labile nature of RNA limits off-target effects and enables dose control. Compatibility with hepatotropic non-viral vectors is convenient for the large scale preparation that will be required for advancing gene editing as a mode of curing chronic hepatitis B. (c) 2020 Published by Elsevier B.V.
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