Gene editing for latent herpes simplex virus infection reduces viral load and shedding in vivo

Martine Aubert, Anoria K. Haick, Daniel E. Strongin, Lindsay M. Klouser, Michelle A. Loprieno, Laurence Stensland, Tracy K. Santo, Meei-Li Huang, Ollivier Hyrien, Daniel Stone and Keith R. Jerome ()
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Martine Aubert: Fred Hutchinson Cancer Center
Anoria K. Haick: Fred Hutchinson Cancer Center
Daniel E. Strongin: University of Washington
Lindsay M. Klouser: Fred Hutchinson Cancer Center
Michelle A. Loprieno: Fred Hutchinson Cancer Center
Laurence Stensland: University of Washington
Tracy K. Santo: University of Washington
Meei-Li Huang: University of Washington
Ollivier Hyrien: Fred Hutchinson Cancer Center
Daniel Stone: Fred Hutchinson Cancer Center
Keith R. Jerome: Fred Hutchinson Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Anti-HSV therapies are only suppressive because they do not eliminate latent HSV present in ganglionic neurons, the source of recurrent disease. We have developed a potentially curative approach against HSV infection, based on gene editing using HSV-specific meganucleases delivered by adeno-associated virus (AAV) vectors. Gene editing performed with two anti-HSV-1 meganucleases delivered by a combination of AAV9, AAV-Dj/8, and AAV-Rh10 can eliminate 90% or more of latent HSV DNA in mouse models of orofacial infection, and up to 97% of latent HSV DNA in mouse models of genital infection. Using a pharmacological approach to reactivate latent HSV-1, we demonstrate that ganglionic viral load reduction leads to a significant decrease of viral shedding in treated female mice. While therapy is well tolerated, in some instances, we observe hepatotoxicity at high doses and subtle histological evidence of neuronal injury without observable neurological signs or deficits. Simplification of the regimen through use of a single serotype (AAV9) delivering single meganuclease targeting a duplicated region of the HSV genome, dose reduction, and use of a neuron-specific promoter each results in improved tolerability while retaining efficacy. These results reinforce the curative potential of gene editing for HSV disease.

Date: 2024
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DOI: 10.1038/s41467-024-47940-y

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