DNA cleavage enzymes for treatment of persistent viral infections: recent advances and the pathway forward.
Treatment for most persistent viral infections consists of palliative drug options rather than curative approaches. This is often because long-lasting viral DNA in infected cells is not affected by current antivirals, providing a source for viral persistence and reactivation. Targeting latent viral DNA itself could therefore provide a basis for novel curative strategies. DNA cleavage enzymes can be used to induce targeted mutagenesis of specific genes, including those of exogenous viruses. Although initial in vitro and even in vivo studies have been carried out using DNA cleavage enzymes targeting various viruses, many questions still remain concerning the feasibility of these strategies as they transition into preclinical research. Here, we review the most recent findings on DNA cleavage enzymes for human viral infections, consider the most relevant animal models for several human viral infections, and address issues regarding safety and enzyme delivery. Results from well-designed in vivo studies will ideally provide answers to the most urgent remaining questions, and allow continued progress toward clinical application.
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, E5-110, Seattle, WA 98109, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA. Electronic address: nweber@fhcrc.org.
Nicholas D
ND
Weber
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, E5-110, Seattle, WA 98109, USA. Electronic address: maubert@fhcrc.org.
Martine
M
Aubert
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, E5-110, Seattle, WA 98109, USA. Electronic address: cdang@fhcrc.org.
Chung H
CH
Dang
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, E5-110, Seattle, WA 98109, USA. Electronic address: dstone2@fhcrc.org.
Daniel
D
Stone
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, E5-110, Seattle, WA 98109, USA; Department of Laboratory Medicine, University of Washington, Seattle, WA 98195, USA; Department of Microbiology, University of Washington, Seattle, WA 98195, USA. Electronic address: kjerome@fhcrc.org.
Keith R
KR
Jerome
D000818:Animals; D053837:DNA Cleavage; D004279:DNA, Viral / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D014777:Virus Diseases / Q000628:therapy*; D017735:Virus Latency; D018406:Virus Physiological Phenomena
D004279:DNA, Viral
Animal models; DNA cleavage enzymes; Endonuclease; Gene therapy; Gene therapy delivery; Persistent viruses; Targeted mutagenesis