Could Gene Editing Cure Herpes One Day?

Herpes is shockingly common. Recent estimates suggest at least half of all Americans have HSV-1, or oral herpes, which usually manifests as cold sores on or around one’s mouth, but can spread to someone else’s genitals through oral sex or to other parts of the body. Up to a fifth of all Americans have HSV-2, or genital herpes, although only 87 percent of HSV-2 cases are ever clinically diagnosed, thanks to the fact that many people infected by the virus never develop symptoms.

These symptoms can include painful sores that crop up on or around one’s genitals or anus, and usually take weeks to heal. They can also cause flulike symptoms the first time they appear, and for about a third of people with symptoms, reoccur several times a year. In worst-case scenarios, genital herpes can drastically increase someone’s risk of acquiring HIV, among other infections like encephalitis or eye diseases, or spread from a mother to an infant during childbirth, risking post-natal death. But even best-case asymptomatic herpes carriers can infect others, who may suffer more from the virus.

Unfortunately, herpes is also shockingly intractable. Scientists have been working on vaccines to prophylactically help our immune systems ward off herpes infections, or to therapeutically help them fight the virus back once it has taken up shop in our bodies, for more than 80 years—to no avail. Repeated failures for supposedly promising new techniques, including one vaccine that flared out spectacularly about a decade ago after a pharma giant sunk millions of dollars and years of effort into research, have cast a gloom and doom aura over this field of research.

In recent years, though, a few researchers have started to hope that we might be on the cusp of not just developing a therapeutic vaccine to protect against or manage the virus, but to actually cure those infected with it. This potentially radical breakthrough comes courtesy of gene editing—which is likely unsurprising, given how hot and promising this field has been of late.

Before diving into the potential of gene editing to obliterate a herpes infection, however, it’s worth exploring why exactly vaccines have such a hard time tackling the virus. When herpes enters our bodies, it uses strategies it has evolved to evade our immune systems. “HSV-1 hides in the trigeminal ganglia, a ball of neuronal cell bodies close to our ear, and HSV-2 hides in the dorsal root ganglia, a ball of neuronal cell bodies well-hidden on either sides” of our spines, says Sita Awasth, a University of Pennsylvania herpes vaccine researcher.

Our immune systems can’t chase the virus there. Or perhaps they could, if we trained them to, but in so doing they would also be attacking out nervous systems too. So herpes is free to chill there, then periodically surge back out towards our skin, creating symptoms like painful sores or just shedding out innocuously to infect others.

A few vaccines seem to be making progress when it comes to blocking initial infections. Awasthi’s colleague, Harvey Friedman, has seen great success in lab tests with a vaccine that tries to train our immune systems to better recognize and fight herpes and its evasion tactics from the start. But his research seems to be moving relatively slowly. And once someone is infected, the best vaccines and other antiviral therapies can offer is aid in tackling herpes when it comes partially out of hiding in our nerve cells, rather than a full-on cure for the infection.

Therapies like acyclovir (developed in 1982) or valcyclovir (developed in 1995) are pretty effective at this control task; they can reduce the number—and severity—of outbreaks someone with symptomatic herpes has by 70 to 80 percent per year. But this does little to nothing to tackle the psychological stress and social stigma many experience just because they know they carry the virus.

Enter gene editing. The concept is deceptively simple: “With DNA editing,” explains Keith Jerome of Seattle’s Fred Hutchinson Cancer Research Center, researchers can go into infected nerve cells “with ‘molecular scissors’ and either clip out parts of the virus, or basically destroy the entire thing.” With the virus effectively neutered or obliterated, someone with herpes is then functionally cured.

Research into gene editing as a form of treatment for persistent viruses is nothing new. Jerome has been at it for over a decade. But the tools he and other old school gene editors use—in his case, a class of enzyme called meganucleases—are relatively difficult to manipulate. “If you want to change them to target something you’re interested in,” he explains, “a part of the human genome or a virus, you have to do a bunch of protein engineering [to] change the structure [of the enzyme] to get it to recognize what you want. That’s difficult. It takes, typically, months.”

Interest in gene editing has exploded over the past five years, though, thanks to the emergence of CRISPR Cas-9, a new gene editing tool which, as Jerome explains it, is much easier and cheaper to manipulate. In the last three years especially, the democratization of gene editing offered by CRISPR has led to a flurry of researcher—and funding agency—interest in gene editing cures.

CRISPR-based therapies for herpes, however, haven’t shown much promise to date. Although they could improve, Jerome stresses, the best attempts to use CRISPR to tackle herpes in infected mice cells in the lab have only managed to knock out two to four percent of the virus. Such a low success rate, Awasthi stresses, would not really be much of a cure—or even a therapeutic help.

Even though CRISPR has stoked interest in the field, Jerome notes that in the past few years other gene editing tools have seen massive spikes in efficiency when it comes to herpes cures. His therapy, he adds, has gone from five percent to over 90 percent effective at eliminating herpes in mice cells in the lab over the last two and a half years.

“Because they’re smaller proteins” than CRISPR Cas-9, he explains, his meganucleases have an easier time working their way into target zones where they can find the virus and get rid of them, even if they have taken more effort to coax into a workable form. “Although they’re hard to make,” he stresses, “if you have a virus you’re going after, it’s worth the effort. If you’re making a therapeutic that you ultimately want to give to people, once you have it, you have it.” That means you don’t need CRISPR’s easy malleability. “We haven’t exhausted all of the ways to optimize things,” he adds. He’s hopeful that he can get his gene editing tools to eliminate up to 99.9 percent of latent herpes.

Despite this progress and potential, a gene editing cure for herpes is still likely a long ways off. As Awasthi points out, all research in the field to date has been done in animal cells in a lab, which are not always a great proxy for the living human body at large. Jerome hopes to move on to human trials and optimization in the not-too-distant-future—he wisely avoids putting a specific timeframe on a process that can encounter all sorts of unexpected bumps and delays.

But he notes that, in human tests, they’ll need to be very careful and deliberate. For instance, they’ll need to figure out all of the possible side effects of such a therapy, which are currently largely unknown, but could include anything ranging from general pain to unintended genetic mutations if one’s ‘molecular scissors’ somehow stick around in a nerve cell too long and later run amuck. Researchers also need to figure out exactly how much herpes a gene editing therapy would need to reliably wipe out in nerve cells to be a real cure: would 90 percent functionally kill the virus, or do you need to go to a full 100?

Popular focus on CRISPR also puts a few minor obstacles in the path of researchers like Jerome. People (including potential boosters) don’t always realize there are viable non-CRISPR gene editing tools worth exploring, he says. “I sometimes have to educate even other scientists.”

Even if Jerome or someone like him does create a cure, that won’t mean that herpes is done and dusted. Considering how easy it is for herpes to go undetected in one person, then spread to someone else on whom it might wreak havoc, we still need effective preventative vaccines, to make a real, lasting, and meaningful impact on public sexual health, Awasthi stresses. Furthermore, if gene editing therapies plateau at 99 percent efficacy and the remaining one percent of herpes in a body’s nerve cells still proves to have the potential to cause issues, an effective vaccine could be a vital adjunct treatment “to control those last few viruses,” Jerome notes.

Still, for the gloom-and-doom world of herpes treatment research, recent developments in gene editing cures are exceptionally promising and exciting. “People should be excited,” Jerome argues, even if such a cure is tentative and years out.

“I’m actually far more optimistic than I was five years ago,” he says, adding that he’s now fairly certain that, within his lifetime, we can cure herpes.

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