CRISPR Prime Editing Rewrites DNA in the Human Body for the First Time

Prime editing is finally ready for prime time. Introduced in 2019, the CRISPR-based gene editor wowed scientists with its versatility and precision. A search-and-replace engine for the human genome, it can swap individual DNA letters, insert new genetic instructions, or delete chunks, all with minimal damage to the genome. In theory, it could correct up to 89 percent of known genetic variants associated with disease.

Now, scientists at Prime Medicine in Cambridge, Massachusetts, are testing the technology’s ability to make edits inside the body for the first time. In a global clinical trial for Wilson disease, the team is giving participants a prime editor that directly rewrites DNA in liver cells. The first patient received an infusion earlier this month, but results showing whether it’s safe and how well it works aren’t expected until next year.

The therapy has “the potential to offer patients a one-time curative treatment, ideally before irreversible liver and neurological damage occur,” Mohammed Asmal, chief medical officer of Prime Medicine, said in a press release.

Version Update

Gene editing made history in 2024 when regulators approved Casgevy for the inherited blood disorders sickle cell disease and beta thalassemia. It was the first CRISPR-based treatment to receive the green light. Casgevy uses CRISPR-Cas9 to edit blood stem cells outside the body, switching on a fetal form of a blood protein that compensates for the faulty adult version.

The classic version of CRISPR cuts through both DNA strands. Over the years, scientists have expanded on it significantly. Rather than simply disabling a gene, some variants can insert new genes, flip DNA sequences, or delete millions of DNA letters across a chromosome. Other spin-offs target RNA—the messenger molecule delivering genetic instructions—rather than DNA itself.

But for all these upgrades, CRISPR-Cas9 has a glaring weakness: It’s rough on the genome. Much of what we call “editing” is actually cells scrambling to repair broken DNA strands. Sometimes, they botch the job. In one glaring example, a single cut triggered the loss of large portions of a chromosome, which one expert called “genome vandalism.”

To rein in collateral damage, scientists redesigned the system to nick only one DNA strand. Base editing emerged as a powerful alternative. Here, the tool swaps one DNA letter for another without deliberately breaking the double helix.

Base editing made medical history last year, when doctors gave a baby, KJ Muldoon, a custom-made base editor to treat a life-threatening genetic disorder. Delivered to his cells inside lipid nanoparticles, the editor corrected a DNA mutation and eased his symptoms in weeks. Multiple clinical trials are now exploring base editing for other diseases. However, the technology can make only certain types of DNA-letter swaps.

Prime editing takes the concept a step further, turning the gene editor into a genetic word processor.

Like base editors, prime editing cuts a single DNA strand. A second component, pegRNA, carries a blueprint of the desired edit and steers the machinery to its target. Once there, a third component copies the RNA instructions into DNA, which the cell can incorporate into its genome. In a variety of tests, the inventors showed prime editing could swap any DNA letter for another, add new genetic code, or delete short stretches with high precision.

But there was a problem. Prime editors are hefty molecular machines. Getting them into the right cells is tricky.

Special Delivery

In prime editing’s first medical foray, researchers targeted chronic granulomatous disease, a rare immune disorder. Here, genetic defects prevent certain microbe-fighting immune cells from attacking invaders, leaving patients vulnerable to dangerous infections.