In late 2021, Amber Salzman interviewed for a job she had no intention of accepting. A relatively new startup, called Epicrispr Biotechnologies, was looking for a CEO and was keen to select Salzman – who had decades of experience in the pharmaceutical industry – for the role. She had said yes to the meeting only as a favor to a recruiter, who had helped her fill a key position at another company she had worked with. Joining the start-up did not excite him.
Halfway through the meeting, she changed her mind. Salzman had seen Stanley Qi, the founder of Epicrispr, drawing diagrams on a whiteboard explaining that the company wanted to create gene therapy — not by changing the code itself, but by changing the chemical markers attached to DNA, which can turn genes on or off. Salzman then asked another team member, “‘What disease are we pursuing?’ » And she said ‘FSHD’.
Salzman knew the situation all too well. FSHD, short for facioscapulohumeral muscular dystrophy, is an inherited disorder in which muscle problems first start in the face and upper body and can spread to other parts, sometimes requiring the use of a wheelchair. Salzman’s husband of more than 35 years had several cousins and a grandmother with the disease, although he did not inherit it himself.
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His family’s experience with this disorder was always on his mind, but Salzman never saw a way to make a difference in his previous positions: “At the time, no one really understood what was causing this. » But the conversation with Epicrispr gave him the opportunity to address the disease.
She accepted the company’s offer to become its general manager. In doing so, Salzman joined a specialized group of drug developers trying to advance a technique called targeted epigenetic editing. The idea is to remove or add epigenetic markers – essentially chemical groups that sit on top of DNA (and the proteins it is wrapped around). Depending on the chemical group present or absent, genes can be turned on or off.
Some existing drugs influence epigenetic markers, but these drugs act broadly and lack specificity. This new group of scientists has found ways to precisely modify epigenetic markers influencing specific genes. Epicrispr, based in South San Francisco, California, is one of several companies working on such therapies. At the International FSHD Research Congress, held in late June in Chicago, Illinois, the organization was one of the first to announce data from an epigenetic editing trial.
Epigenetic markers have a huge impact on how our cells interpret DNA. Changing a genome’s epigenetic tags is like using an audio mixer to modify a piece of music so that it resembles the works of composer Franz Schubert or pop star Taylor Swift, says biologist Fyodor Urnov of the University of California, Berkeley. Urnov has contributed to the use of various gene editing technologies and co-founded an epigenetic editing company called Tune Therapeutics in Seattle, Washington.
The tools being deployed in this new era of epigenetic editing bring something new to standard gene editing, which involves using the CRISPR system to cut DNA. This system is precise, but it can still lead to cuts in the wrong place, which can disrupt or damage genes. “Epigenetic editing is a really exciting therapeutic concept because there is no chance of off-target DNA mutations, as there is with gene editing,” says Jessica Tyler, a molecular biologist at Weill Cornell Medicine in New York.
Most epigenetic editing platforms, rather than making changes to the DNA itself, modify markers attached to DNA. This is thought to be safer for two reasons: first, the system cannot mistakenly cut in the wrong place, and second, it reduces the possibility that the DNA can rearrange itself, which is a risk whenever DNA breaks. Furthermore, preclinical experiments on human cells show that epigenetic modifications are reversible.
But epigenetic forces are powerful, and researchers must proceed with caution, says Yann Joly, a bioethicist who directs the Center for Genomics and Policy at McGill University in Montreal, Canada. “Epigenetic regulation plays a central role in development and reproduction,” he explains. The community must ensure that epigenetic therapies are administered safely and without unintended consequences, he says.
It’s absolutely true
In 2012 and 2013, several independent groups published a series of papers describing the original CRISPR-Cas9 editing system and its application. In conventional CRISPR, a guide RNA finds the target sequence in the genome, and a Cas9 enzyme then cuts the DNA. These findings have attracted much attention because of their potential to rewrite DNA. But at the time, most people may not have understood that biologists were already thinking about how to adapt CRISPR editing to modulate gene expression, rather than breaking or rewriting the genetic code.
One of those biologists was Qi, who had worked in the lab of CRISPR pioneer Jennifer Doudna at the University of California, Berkeley. He wanted to know how to control the programming of a cell, rather than modifying its code.
He launched his lab at the University of California, San Francisco (UCSF) and began studying how to modify the CRISPR-Cas9 system so that it could still latch on to targeted DNA but not cut the sequence after reaching it. In 2013, Qi and his colleagues, including biochemist Jonathan Weissman, also at UCSF at the time, and Doudna, opted for modifications to achieve this goal. They called the repurposed Cas9 “dead” because it lacked its normal enzymatic cutting activity.
Next, the team deployed a guide RNA to drive the dead Cas9 to the right place, along with a protein that could turn gene expression on and off. Tests showed that the system worked in human cells and was very accurate.5. “That’s when we realized this was a transformative tool,” says Weissman, who now works at the Massachusetts Institute of Technology in Cambridge.
Shortly after the publication of these key papers, Qi moved his laboratory to Stanford University in California. There, he continued to improve the Dead-Cas9 system and found a smaller version – called Cas12F – that could more easily be delivered to cells (the typical Cas9 protein, from bacteria, is relatively large).
Qi and his teammates discovered Cas12F in archaea, organisms that resemble bacteria in some ways but are evolutionarily distinct and have different cell walls. While Cas9 is made up of about 1,300 amino acids, Cas12F contains about 500. To deliver the payload to cells, the recipe for dead Cas12F is encoded into a virus, known as an adeno-associated virus, which is considered harmless to the body. The virus is infused into the body and the cells then produce the Cas12F construct themselves. The protein then goes to work on the target epigenetic markers.
Meanwhile, the company Weissman co-founded, nChroma in Boston, Massachusetts, has made improvements to another component of the system: the methyltransferase element, which modifies epigenetic markers. The company hasn’t revealed which one it uses, but says it’s efficient and small. “Frankly, I think it’s part of our secret sauce,” says Jenny Marlowe, director of development at nChroma.
Treatment trials
In 2025, a team including nChroma scientists published a study in mice and monkeys showing that their approach worked.6. The team’s epigenetic editing system, encapsulated in lipid nanoparticles and administered intravenously, could override the production of a protein called PCSK9, which promotes “bad” cholesterol. A single injection reduced levels of this type of cholesterol in monkeys by about 70%.
Other epigenetic editing therapies are currently in clinical trials. In January, nChroma began administering the first doses of an experimental epigenetic silencer against the hepatitis B virus to people with chronic infection. According to the World Health Organization, an estimated 240 million people worldwide have chronic hepatitis B, which can cause liver failure and cancer. A vaccine exists, but 2019 data suggests that 15% of children worldwide do not receive the full vaccination schedule, and a growing number of parents in countries like the United States are withholding it from their children due to health misinformation.
To make matters worse, existing drugs cannot completely eliminate hepatitis B from the body, because the pathogen has a nasty trick up its sleeve: pieces of its genome integrate into a person’s DNA and, from there, generate proteins that alter the immune response against it.
The nChroma Silencer aims to help the body get rid of hepatitis B by neutralizing both the virus in the wild and the parts of the virus that have embedded themselves in a person’s DNA, particularly in the liver. According to nChroma, this will prevent hepatitis B from tricking the body and allow the immune system to attack it. “The bar is very high in terms of the number of cells that actually need to be silenced in the liver,” notes Melissa Bonner, scientific director of nChroma Bio. “We think this must be the vast majority of cells.”
nChroma is currently exploring the use of gene editing systems in addition to CRISPR, such as zinc finger nucleases, which can be engineered to change gene expression without cutting DNA.
Tune Therapeutics is also among the companies targeting hepatitis B through epigenetic editing. In late May, he presented data at the European Association for the Study of the Liver congress in Barcelona, Spain, showing that his epigenetic silencing therapy caused levels of hepatitis B markers — such as its RNA intermediate and one of its viral proteins — to drop to undetectable levels in some recipients.
After Salzman began working at Epicrispr, she encouraged the company to conduct real-world testing of its FSHD treatment, called EPI-321. By spring 2025, the company had received approval from the U.S. Food and Drug Administration to begin trials of this therapy. During the summer, the p first participant received a dose. Since then, more than half a dozen adults with FSHD have received the initial dose. The company plans to enroll 12 participants in total.
At the June meeting, the company announced that it had evaluable data from the first three clinical trial participants and that after six months, a single dose of its treatment caused a statistically significant increase in whole-body lean muscle mass in all three people. The volunteers saw an estimated average increase of around 0.4 kilograms in muscle mass. “We were surprised to see at the six-month visit – because it’s the first time we’ve done an MRI [magnetic resonance imaging] “The patients were actually gaining muscle mass,” says Salzman. This contrasts with previous data collected from around 100 people with FSHD, which predicted that, without any intervention, participants would typically have lost muscle at this stage.
FSHD is suitable for treatment with epigenetic modification because it is thought to be caused in part by abnormal epigenetic markings. People with FSHD typically have a shorter-than-normal version of a particular piece of DNA on chromosome 4 – a truncation that also removes epigenetic markers. Usually there are at least ten repeats of this region, known as D4Z4, and they are heavily marked with methyl groups. These marks tell D4Z4 to silence a gene called CHEF 4which would otherwise produce a protein toxic to the muscles. So when these markers are not present, the D4Z4 region cannot do its usual job and the toxic protein causes muscle deterioration. EPI-321 orchestrates the addition of missing methyl groups to the D4Z4 region.
It is estimated that around 870,000 people worldwide have some form of FSHD, but it is not always caused by the same mutation. This gives epigenetic editing a crucial advantage, according to Salzman. Regular gene editing, which directly modifies DNA, must be tailored to the precise sequence error in the affected gene in a given person. The epigenetic editor EPI-321, in contrast, binds to a portion of the DNA slightly upstream of the mutated D4Z4 region. This makes it a more universal treatment for FSHD, because everyone with the disease has an identical sequence in this upstream part, Salzman says.
FSHD is not the only disease involving irregular epigenetic patterns. Epigenetic dysregulation is also associated with worsening symptoms of Huntington’s disease and Parkinson’s disease7. And beyond that, Salzman says Epicrispr seeks to treat conditions that are not at all known to involve epigenetic abnormalities. The strategy involves linking an epigenetic editor to the regulatory regions upstream of mutated genes, turning them on or off, while providing a functional version of the gene in the same package. For example, the company is developing a treatment for a progressive eye disease called autosomal dominant retinitis pigmentosa 4, in which it plans to delete a mutated gene encoding rhodopsin, a protein that helps eyes see in dim light, and give cells a working copy — all without directly altering the DNA. The company’s treatment for Duchenne muscular dystrophy, meanwhile, is designed to increase the activity of a gene to restore muscle stability and protect those tissues from further damage.
Several other biotechnology companies are moving into epigenetic editing. Scribe Therapeutics in Alameda, California, co-founded by Doudna, who won a Nobel Prize in chemistry for his discoveries in gene editing1has an epigenetic silencing platform called ELXR. This is a treatment for high cholesterol, targeting the PCSK9 gene, which nChroma therapy also looks for. Epigenic Therapeutics in Shanghai, China, is also developing epigenetic editing treatments to lower cholesterol, as well as a treatment for hepatitis B. General Control, a San Francisco startup, aims to treat widespread age-related diseases (although it hasn’t revealed much about which ones). The reason, explains Lada Nuzhna, general director of General Control, is that the characteristics of aging are often associated with genetic expression gone awry, rather than a mutation in a single gene.
Epigenetic editing tools seem create lasting changes to DNA markers. “Once epigenetic modification of DNA methylation is achieved, the cells’ own machinery should maintain the modified DNA methylation pattern during subsequent cell divisions,” explains Tyler. Certain enzymes help copy existing methylation patterns from the original DNA strands to the new strands of daughter cells.
But the powerful nature of epigenetic editing is also a reason to closely monitor its safety, according to Joly. “Epigenetic editing may seem safer than genome editing because it does not involve cutting DNA, but ‘non-cutting’ should not be equated with ‘risk-free’,” explains Joly. He adds that turning off the wrong gene could have significant consequences – and that this is particularly true if the gene mistakenly silenced is a tumor suppressor or is involved in immunity or development. Tyler also cautions that researchers must be vigilant to ensure that no unintended effects occur. “Off-target epigenetic modification could potentially aberrantly alter gene expression,” she notes.
Salzman knows from his extended family’s history how high the stakes are. “If everything goes in our favor,” she says, Epicrispr could apply for a license to sell its FSHD therapy in a few years. “It could be marketed before 2030,” she adds. “That’s the best-case scenario, but it’s not that far off.”
