Super-precise CRISPR tool enters US clinical trials for the first time

A high-precision successor to CRISPR genome editing has reached a milestone: the technique, called base editing, has made its US debut in a clinical trial. The trial tests more complex genome edits than those performed in humans to date.

Trial organizers announced on 5 September that the first participant had been treated using immune cells with four base-edited genes, equipping the cells to better target and destroy tumours. The hope is that the approach can tame trial participants’ difficult-to-treat form of leukaemia and serve as a gateway to more complex edits in the future.

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“There are things still to be built into these cells to make them easier to use and persist longer,” says Waseem Qasim, a paediatric immunologist at the University College London Great Ormond Street Institute of Child Health. “And with so many groups working on it, things will get incrementally better.”

It’s been a strikingly quick evolution from the first reports of base editing in 2016 to clinical trials, but the CRISPR field has never been one to dawdle. And while researchers develop ever more intricate gene-editing therapies, they are also keeping a wary eye on drug regulators in the United States and Europe. Officials in both places are expected to decide this year whether to approve the first CRISPR–Cas9 therapy, a treatment for sickle-cell disease.

That decision “will clarify for the field what needs to happen to meet the bar with regulators”, says John Evans, chief executive officer of Beam Therapeutics, the base-editing company in Cambridge, Massachusetts that made the 5 September announcement.

CRISPR drawbacks

Base editing’s appeal lies in its specificity and potential safety. The most common form of CRISPR–Cas9 genome editing relies on an enzyme called Cas9. Inside cells, Cas9 cuts both strands of the DNA double helix at a particular site. The cell’s DNA repair machinery then mends the cut, sometimes inserting or deleting a few DNA letters, or ‘bases’, as it does so. Such mistakes during repair often disable the gene, which is handy for some gene-editing applications. But researchers cannot control exactly how the cell repairs its DNA, and cannot predict the resulting DNA sequence.

Base editing, by contrast, generally cuts only one strand of DNA, and the base editor converts DNA bases at the break site to a particular type. The result is more control over the edited sequence, and less cell death from damaged DNA.

This has also opened the door to creating multiple edits in the same cell. Such multi-site editing can be risky with CRISPR–Cas9, because each edit requires breaking both strands of DNA. Multiple double-stranded breaks can create a mix of genomic fragments that the cell might not be able to properly stitch back together. The result can be a dangerous level of genomic chaos, with pieces of chromosomes in the wrong order or location — or missing altogether.

Anti-cancer cells get an upgrade

Beam Therapeutics and another research team, led by Qasim, are attempting to improve CAR-T-cell therapy, which is already used to treat a variety of cancers. It typically involves removing a sample of a person’s own T cells, engineering them to produce cancer-targeting proteins called chimeric antigen receptors (CARs) and then reinfusing the cells into the body.

The therapy has been successful in treating some types of leukaemia, but not a rare cancer called T-cell leukaemia. People with advanced disease often do not have enough healthy T cells to generate a bespoke therapy, says Caroline Diorio, a paediatric oncologist at the Children’s Hospital of Philadelphia in Pennsylvania.

To sidestep that problem, Qasim’s team collected T cells from healthy donors and edited three sites in the cells’ genomes. The edits were designed to reduce the chance that the recipient’s immune system would reject the donor cells. The edits also aimed to keep the CAR T cells from destroying each other, and to allow the cells to survive when participants are treated with a cancer drug that can kill the T cells. The trial, which is taking place in the United Kingdom, treated its first participant in 2022.

The team reported¹ in June this year that the edited CAR T cells were active in the first three participants that they treated, although one participant subsequently died from an infection.

Beam’s approach is similar, but adds a fourth edit that is intended to extend how long the engineered cells are active.

Many paths to a better T cell

The list is unlikely to stop there. As researchers learn more about the factors that can influence T cell responses to cancer, they are generating a growing list of fresh edits that might help CAR T cells to fight tumours. “The technology is there,” says Evans. “The issue becomes more biological: what do you want to edit?”

Even so, researchers will be watching these first clinical trials closely. “Any kind of gene editing should come with serious concern for possible safety impacts,” says Diorio, who is an investigator on the Beam trial.

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A recent study² found that base editing can cause double-stranded DNA breaks, although it does so far less often than CRISPR–Cas9 does. The study also identified other unwanted DNA changes that CRISPR–Cas9 did not cause. “It is something to consider, but it doesn’t mean that we should not be using base editing,” says Luigi Naldini, a gene-therapy researcher at the San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, and lead author on the work. “There is no perfect method.”

But newer base editors make fewer unwanted edits, says Evans. Even so, researchers are still hunting for ways to improve base-editing technology, says chemical biologist Alexis Komor at the University of California, San Diego. Another biotechnology company called Verve, also based in Cambridge, Massachusetts, is conducting a clinical trial of base editing performed directly in the body by using lipid nanoparticles to deliver the base-editing components. And laboratories are testing ways to reduce unwanted changes and expand the number of edits that are possible using the technique. “It’s worthwhile to have different tools that function via different mechanisms,” Komor says. “Some cell types could be more amenable to editing with one versus another.”