CRISPR, a gene-editing technology, is emerging as a potential solution to the challenges of herpes viruses. These widespread viruses establish lifelong infections, and current treatments primarily manage symptoms rather than offering a cure. This article explores how CRISPR is being investigated as a therapeutic approach to target and eradicate herpes viruses.
Understanding Herpes Viruses
Herpes viruses are a family of DNA viruses that establish lifelong infections. Common members include Herpes Simplex Virus Type 1 (HSV-1), responsible for oral herpes, and Herpes Simplex Virus Type 2 (HSV-2), which causes genital herpes. Varicella-Zoster Virus (VZV), the cause of chickenpox and shingles, is also part of this family.
A defining characteristic of herpes viruses is their capacity for latency, where the viral DNA lies dormant within nerve cells. Periodically, these latent viruses can reactivate, leading to recurrent outbreaks of symptoms. This cycle of latency and reactivation makes herpes infections difficult to eliminate with conventional antiviral drugs, which primarily target active viral replication.
CRISPR’s Approach to Herpes
CRISPR and its associated Cas proteins, provides a precise method for editing DNA. This system functions like molecular scissors, guided by a small RNA molecule to specific DNA sequences. Once guided to the target, the Cas protein makes a cut in the DNA, which can disrupt or remove the targeted sequence.
For herpes viruses, CRISPR is engineered to disrupt their life cycle. One strategy involves disrupting the latent viral DNA within host cells to eliminate the viral genome. Another approach disrupts viral gene expression, preventing replication and new viral particle production. By targeting genes like UL30, UL39, ICP0, ICP4, or ICP27, CRISPR can inhibit the lytic (active replication) phase of the virus.
CRISPR can also target specific viral genes to prevent reactivation from latency, reducing recurrent outbreaks. Different CRISPR systems, such as Cas9 and Cas12a, are optimized for these strategies. Using multiple guide RNAs simultaneously (a “multiplex” strategy) has shown enhanced antiviral effects, making it harder for the virus to escape treatment.
Current Research and Clinical Progress
CRISPR research for herpes viruses shows advancements in laboratory and animal models. In vitro studies using human cell lines have demonstrated CRISPR’s ability to inhibit herpes simplex virus replication and, in some cases, eliminate viral genomes. Combining two guide RNAs targeting essential HSV-1 genes has completely impaired the production of new infectious particles from human cells.
Progress has also been observed in animal models, including mice, guinea pigs, and rabbits. In mouse models of orofacial and genital infection, gene editing with meganucleases delivered by adeno-associated virus (AAV) vectors has reduced latent HSV DNA by 90% or more. In a rabbit model of recurrent HSV-1 keratitis, a combination of guide RNAs delivered by AAV vectors reduced viral shedding in tear films by 75% and suppressed corneal lesions by 91%.
While most research remains in preclinical stages, there is progression towards human trials. As of February 2025, over 150 gene-editing trials are active across various therapeutic areas, including viral diseases. One clinical trial (NCT04560790) has involved injecting an HSV-1-targeting CRISPR formulation into the cornea of three patients with severe herpes stromal keratitis during corneal transplantation. This preliminary human study indicated no detectable CRISPR-induced off-target cleavages or systemic adverse events for an average of 18 months, with HSV-1 remaining undetectable during the study period.
Future Prospects and Hurdles
CRISPR holds potential for a functional cure or even complete eradication of herpes. By targeting and disrupting the viral genome, CRISPR could offer a permanent solution beyond symptomatic relief from current antivirals. This approach could prevent active outbreaks and lifelong viral persistence in nerve cells.
Despite this promise, significant challenges must be addressed before CRISPR therapies become widely available. A primary hurdle involves developing effective delivery methods to transport CRISPR components to infected cells, especially neurons where herpes viruses establish latency. Viral vectors, such as adeno-associated viruses (AAVs) and lentiviruses, are common delivery vehicles, but their packaging capacity can be limited, especially for multiple guide RNAs.
Ensuring CRISPR editing precision to avoid off-target effects (inadvertent editing of human genes) is another major concern. Careful consideration of Cas protein expression duration and specificity is ongoing to minimize off-target risks. The body’s immune response to CRISPR components (Cas protein and viral vectors) also requires investigation to prevent adverse reactions that could compromise treatment efficacy or safety.
Scalability and cost present practical obstacles, as producing and distributing affordable gene therapies for a widespread condition like herpes will be complex. Finally, the rigorous regulatory approval process for novel gene therapies, involving extensive safety and efficacy testing, will be lengthy before CRISPR-based herpes treatments can reach the public.