Instead of cutting DNA and changing the genetic sequence, biotech companies are trying to add or remove chemical tags that turn genes on and off. Initial trials in muscular dystrophy and viral hepatitis show early signs, but questions about long-term safety and efficacy remain.
Instead of cutting DNA and changing the genetic sequence, biotech companies are trying to add or remove chemical tags that turn genes on and off. First experiments inMuscular Dystrophy And bדלקת כבד נגיפית Showing early signs, but questions of long-term safety and efficacy remain open
Bluetooth technology CRISPR It became famous for its ability to cut DNA at a specific point and change the genetic code. Now a new direction is developing: using the CRISPR navigation system to change the activity of genes, without changing the DNA sequence itself.
The approach is called epigenome editing. It is based on changing the chemical marks and molecular structures that determine which genes will be active, to what extent, and in which cells.
Several biotech companies have already begun testing such treatments in humans. Initial targets include a hereditary muscle disease and chronic viral hepatitis. Other programs, including a potential treatment for high cholesterol, are still in the preclinical stages.
What is the epigenome?
Almost all cells in the body contain the same DNA sequence. However, a muscle cell, a liver cell, and a nerve cell activate different sets of genes.
One of the mechanisms that makes the differences possible is the epigenome: a layer of chemical marks attached to DNA and the proteins around which it is packaged. These marks do not change the genetic letters, but they can increase or decrease the activity of a gene.
A key example is DNA methylation. This process attaches methyl groups to specific regions of the genome. In many cases, methylation helps silence genes and prevent them from being read.
Unlike a genetic mutation, an epigenetic mark can change throughout life. It may also persist for a long time and be passed on to new cells when the cell divides.
Scissor-free navigation system
In the classic CRISPR system, an RNA molecule guides the Cas9 protein to a specific site in the genome. Cas9 cuts both strands of DNA, and the cell's repair mechanisms create the desired change.
Epigenome editing often uses a deactivated version of the CRISPR protein. The protein is still able to find the genetic address, but does not cut the DNA.
An enzyme that can add methylation, remove an existing mark, or change chromatin packaging is attached to the protein. This allows one to attempt to silence a harmful gene or activate a gene that is lacking activity.
Some companies use other binding proteins instead of CRISPR. The principle is similar: one system locates the address in the genome, and a second system changes its epigenetic environment.
Attempt to silence a toxic gene in muscle disease
One of the most advanced programs in the field is EPI-321 from Epicrispr. The treatment is intended for patients with muscular dystrophy. FSHD – A hereditary disease that causes weakness and gradual loss of muscles in the face, shoulders, arms, and other areas.
In healthy people, the gene DOGE4 Silenced in most cells of the body. In FSHD patients, the silencing mechanism is disrupted, and the gene is activated in muscle cells. The resulting protein damages the cells and contributes to muscle degeneration.
EPI-321 is designed to restore methylation marks to the control region adjacent to DUX4, thereby silencing it. The editing system is packaged in a modified AAV virus and injected in a single infusion.
The trial is in an open-label Phase 1/2 trial, the main goal of which is to test safety, tolerability, and initial signs of biological activity and efficacy.
In June 2026, the company reported that nine patients had received the treatment. The first three patients who could be evaluated after six months had an average increase of approximately 370 milliliters in lean muscle volume.
The company also said that up until the data cutoff, no serious events attributed to the treatment had been recorded. However, these were three patients who were tested in a trial without a control group. Therefore, it is not yet possible to determine whether the treatment is effective or whether the change will be maintained over time.
Attempt to silence a reservoir of hepatitis B virus
Another company, Tune Therapeutics, is testing TUNE-401 in patients with chronic hepatitis B.
One of the main obstacles to treating the virus is a circular DNA molecule known as cccDNA. It remains inside the nuclei of liver cells and serves as a reservoir from which the virus can re-proliferate even after prolonged treatment.
TUNE-401 is designed to reach liver cells and add methylation marks to cccDNA and parts of viral DNA that have integrated into the human genome. The goal is to silence the virus's genetic material, without cutting it.
The treatment is delivered via fat particles containing RNA. After the RNA enters the liver cells, the epigenetic editing system is created for a limited time.
The company reported preliminary results from a phase 1b/2a trial in May 2026. It said that a dose-dependent decrease was observed in several markers of viral activity. In some patients, markers related to cccDNA activity disappeared.
This is also preliminary data presented at the conference and published by the company. It is not yet clear whether the change will lead to a long-term functional cure, and whether the virus will remain suppressed after other treatments are discontinued.
Two companies are targeting the same virus
nChroma has also begun a phase 1/2 trial of an epigenetic therapy against Hepatitis BIts experimental drug, CRMA-1001, is designed to silence both cccDNA and viral DNA that has integrated into the chromosomes of liver cells.
The first patient received the drug in January 2026. At this stage, the goal of the trial is primarily to test safety, tolerability, dosage, and early biological activity.
The fact that two companies are simultaneously developing hepatitis B silencing systems illustrates the commercial and scientific interest in the field. It will also allow for future comparisons between editing systems, delivery methods, and their level of accuracy.
The possibility of reducing cholesterol without changing DNA
One of the early examples that demonstrated the potential of epigenome editing was the silencing of PCSK9, a gene involved in regulating the amount of LDL receptors in the liver.
When PCSK9 activity decreases, the liver is able to remove more LDL cholesterol from the blood. There are now drugs that block the protein, as well as gene editing systems designed to permanently disable the gene.
In animal experiments, epigenetic systems have been able to reduce PCSK9 activity and cholesterol levels without cutting DNA. Companies including Tune and Chroma have shown results in monkeys, but epigenetic cholesterol therapy has not yet reached human clinical trials.
The potential advantage is that it creates a long-lasting effect without creating a permanent mutation. However, it is still unknown how stable the silencing will be over decades, and whether it can be reversed in the event of a side effect.
Why not just edit the garden?
Cutting DNA can create unwanted changes at the target site or elsewhere in the genome. Sometimes the repair that the cell makes is completely unpredictable.
A system that does not cut DNA could reduce some of these risks. It also allows for the control of the intensity of a gene's activity rather than disabling it completely.
Epigenetic editing may also be suitable for diseases where there is no single mutation that can be corrected. In some cases, the problem is excessive activation or abnormal silencing of an entire gene.
But the lack of cutting does not make the treatment risk-free. An epigenetic change in the wrong place can activate harmful genes or silence essential genes. Delivery systems, including AAVs and lipid particles, can also cause immune responses or reach unwanted tissues.
The big question: How long will the change last?
A successful treatment needs to have a long-lasting effect, but not continue to operate unchecked. This is a key challenge in epigenome editing.
In some systems, the editor itself is present in the cell for only a short time. The hope is that the mark it leaves will be preserved through the cell's epigenetic memory mechanisms.
The degree of resistance may vary between dividing and non-dividing cells, and between the liver, muscle, and other tissues. It is also possible that diseases or aging processes may later change the markers again.
Therefore, years of follow-up of trial participants will be required. Researchers will need to check not only whether the treatment works, but also whether the effect remains focused and does not change over time.
Epigenome editing is not yet replacing gene editing. It adds a new tool to the toolbox of genetic medicine: instead of rewriting the code, it attempts to change the way the cell reads it.
Questions and Answers
What is the difference between gene editing and epigenome editing?
gene editing Changes the sequence of DNA letters. Epigenome editing changes chemical marks and structures that determine gene activity, without changing the sequence itself.
Is there already an approved drug based on epigenome editing?
No. As of June 2026, the advanced treatments are in early clinical trials.
Is the epigenetic change reversible?
In principle, epigenetic marks can be added or removed. In practice, a treatment that produces a long-lasting change will not necessarily be easy to reverse in the body.
What diseases are currently being tested?
Early trials are underway in FSHD and chronic hepatitis B. Additional programs are in preclinical development.
Is the technology safer than regular CRISPR?
It avoids the deliberate cutting of both strands of DNA, and therefore may reduce some risks. However, it may create unwanted epigenetic changes and involve risks of transport and immune response.
For the scientific article: Opening the scientific article
More on the subject on the science website
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- Tiny change in DNA caused female mice to develop in a male pathway
- For the first time: Experimental WWOX gene therapy injected into the brain of a baby with severe genetic epilepsy
- Three Israeli researchers were added to the National Academy of Inventors in the US
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