# Meganuclease-mediated gene editing for durable control of HSV-2 infection

> **NIH NIH R41** · CALADAN THERAPEUTICS, INC. · 2024 · $303,731

## Abstract

PROJECT SUMMARY
Herpes simplex virus (HSV) type 2 is the leading cause of recurrent genital herpes which can have severe
physical and psychosocial consequences. The mainline therapy to treat HSV infection, acyclovir, is still
inadequate as it only shortens the duration of lesions during primary or recurrent disease by a few days at
best. Furthermore, while long-term therapy can limit the frequency of lesions, it only reduces the likelihood of
transmission to a sexual partner by about 50%. Most importantly, acyclovir only suppresses viral replication,
but it does not eliminate latent HSV harbored by ganglionic neurons, which is the source for recurrent disease.
Thus, once treatment is stopped viral replication can begin again. We have developed a potentially curative
therapy for latent HSV infection, based on gene editing using HSV-specific meganucleases. Our original work
focused on the treatment of infections and pathogenesis caused by HSV type 1 (HSV-1) and demonstrated
that adeno-associated virus (AAV)-mediated delivery of anti-HSV-1 meganucleases eliminated up to 97% of
latent HSV DNA from ganglia in animal models of latent HSV-1 infection. Furthermore, we showed that this
reduction in ganglionic viral load led to a reduction or even elimination of peripheral virus shedding. In this
Phase I STTR proposal, we plan to extend our anti-HSV gene editing strategy to target HSV-2, the leading
cause of genital herpes. After in vitro selection of a highly active and specific anti-HSV-2 meganuclease, we
will demonstrate its activity in an in vivo guinea pig model of HSV-2 infection, and carefully evaluate the safety
and tolerability of this approach. There is tremendous patient interest in potentially curative therapies, and with
approximately 20 million people infected with HSV-2 in the US alone, the potential impact of a successful
therapy is enormous.
 Specific Aim 1. Select a lead anti-HSV-2 meganuclease variant. We used our established informed
randomized mutagenesis and selection approach to generate 6 lead candidate meganucleases recognizing
HSV-2 as determined by yeast surface display and in vitro cleavage assays. These candidates will be further
assessed and validated using a mammalian cell reporter system for on- and off-target activity, to select a lead
meganuclease for further in vivo development.
 Specific Aim 2. Demonstrate meganuclease antiviral activity in the guinea pig model of HSV-2
infection. The meganuclease showing the best activity and specificity will then be evaluated in the guinea
model of HSV-2 infection for its ability to reduce ganglionic load and HSV shedding and symptomatic disease.
We will also carefully examine treated animals for general tolerability and evidence of therapy-associated
genotoxicity, specifically off-target activity, chromosomal translocations, and integration of sequences in host
genomes.

## Key facts

- **NIH application ID:** 11006727
- **Project number:** 1R41AI186683-01
- **Recipient organization:** CALADAN THERAPEUTICS, INC.
- **Principal Investigator:** KEITH R JEROME
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $303,731
- **Award type:** 1
- **Project period:** 2024-08-05 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11006727

## Citation

> US National Institutes of Health, RePORTER application 11006727, Meganuclease-mediated gene editing for durable control of HSV-2 infection (1R41AI186683-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11006727. Licensed CC0.

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