Gene therapy has faced a fundamental safety problem for years: cutting DNA to repair faulty sections risks permanent damage to the genome. Researchers from UNSW Sydney and St. Jude Children's Research Hospital in Memphis have now found a way around this problem. Their modified CRISPR system switches silenced genes back on without touching the DNA sequence at all.
What silences genes in the first place
Genes are not always active when they should be. So-called methyl groups, tiny molecules that attach to specific stretches of DNA, act as switches: wherever they sit, a gene is blocked. This mechanism is useful in a healthy body, ensuring that liver cells do not produce muscle proteins. In inherited diseases such as sickle cell anaemia and beta-thalassaemia, however, it becomes a problem: beneficial genes are permanently switched off by methylation, even though their DNA sequence is intact.
Classical CRISPR-Cas9 takes a different approach: it cuts the DNA, removes the faulty section and relies on precise repair. This method is effective but irreversible. Errors during a DNA cut leave permanent marks in the genome that cannot be undone. Casgevy, the first globally approved CRISPR therapy from Vertex Pharmaceuticals and CRISPR Therapeutics, uses exactly this approach and costs more than two million dollars per treatment, partly because the safety requirements for DNA-cutting procedures are extraordinarily demanding.
Removing methylation instead of cutting DNA
The new system intervenes earlier. Instead of altering the DNA sequence, it selectively removes the methyl groups that are blocking the target gene. A modified CRISPR enzyme finds the relevant stretch of DNA and detaches the chemical markers without severing the DNA strand. The gene wakes up and begins producing what it is supposed to produce.
The study, published in Nature Communications, provides a finding that goes beyond the method's efficiency. The researchers were able to demonstrate for the first time, through a causal experiment, that methylation does not merely accompany gene silencing but actively causes the blockade. This had been a long-disputed question in epigenetics. The answer has consequences: if methylation is the cause, its removal is the solution, not a workaround.
A further advantage over DNA cutting: epigenetic markers are in principle reversible. If a treatment shows unwanted effects, the genetic information itself remains untouched. That risk of classical CRISPR does not apply here.
Why this matters beyond sickle cell anaemia
Sickle cell anaemia and beta-thalassaemia are the most obvious first targets, because known methylation patterns block specific genes in both conditions. But the potential of the method reaches further. Many diseases, including certain cancers, neurodegenerative conditions such as Alzheimer's and heart muscle diseases, are at least partly caused by faulty gene regulation rather than defective DNA sequences. Classical gene editing, which alters the sequence, offers little help there. Epigenetic editing could fill exactly that gap.
For the cost trajectory of gene therapies, the implications could be substantial. Safety requirements for non-cutting methods are considerably less demanding than for procedures that permanently alter the genome. That makes clinical development faster and cheaper, and therefore more realistic for diseases that have been commercially unattractive because the number of patients is too small relative to development costs.
Years of work still ahead
The path to an approved therapy based on this method still involves significant hurdles. The research group is in the preclinical stage: animal models must demonstrate safety and efficacy before any first-in-human clinical trials become possible. No concrete timeline for such trials has been published yet.
The researchers are simultaneously working to adapt the system for additional disease profiles. The technical foundation, a modified CRISPR enzyme that targets methyl groups rather than DNA strands, is proven. How broadly it can be applied will be determined in the next phase of research. The FDA's approval of Foundayo in April 2026 showed that small molecules with unconventional mechanisms of action can reach the clinic faster than expected. Epigenetic CRISPR research could be similarly ready in several years.