Gene-editing drugs are moving from lab to clinic at lightning speed

One autumn day in 2020 Patrick Doherty was walking his dog up a steep mountain in County Donegal, Ireland, when he noticed he was, unusually for him, running out of breath. The eventual diagnosis was terrifying: amyloidosis, a rare genetic disease that caused a protein, amyloid, to build up in his organs and tissues. The prognosis was even worse: it would cause him years of pain until it finally killed him. In the face of such terrible fortune, though, Mr Doherty had a stroke of luck. He was able to join a trial of a new medical therapy and, with just a single injection, was apparently cured. Now, he continues to walk his dog up that steep mountain in County Donegal every week.

The treatment edited Mr Doherty’s genes using CRISPR-Cas9, a technology that has moved from lab to clinic at lightning speed. Scientists have already used gene editing to improve the vision of people with an inherited condition that causes blindness. They also appear able to cure sickle-cell disease with it, and to restore hearing in deaf mice. This new class of medicines will gather pace in the coming year, tackling cardiovascular disease and cancer. A new generation of more precise and efficient gene-editing tools is also undergoing trials.

Cut and run

CRISPR-Cas9 acts like a pair of molecular scissors that cuts DNA at a precise location. A piece of RNA (a single-stranded version of DNA) attached to the medicine guides the cutting enzyme, Cas9. Once DNA is cut, the cell’s natural repair mechanisms swing into action. Gene-editing medicines commandeer those natural cellular systems and end up replacing an existing (problematic) segment of code with a new (corrected) sequence.

The speed of innovation has been impressive. CRISPR-Cas9 was discovered in the lab in 2012 and just three years later eGenesis, a biotech firm in Cambridge, Massachusetts, had used it to edit pig embryos to create organs more suitable for transplantation into humans. By 2016 a CRISPR-Cas9 therapy was approved for testing in patients with cancer, albeit on immune cells that had been removed from the body, edited to help these cells fight the cancer better, and then returned.

The following year, Vertex and Crispr Therapeutics, pharmaceutical companies based in Boston, Massachusetts, and Zug, Switzerland, said they would co-develop a treatment named CTX001, a treatment for two disorders: sickle-cell disease and beta thalassemia. Both are caused by genetic faults in the instructions for making haemoglobin, a protein that helps red blood cells carry oxygen.

CTX001, known today as Casgevy (exagamglogene autotemcel), arrived on the market in November 2023, priced at $2.2m for a one-time treatment. It involves collecting blood stem cells from a patient, editing a gene within them to restart the production of a type of haemoglobin that is usually produced only when a baby is in the womb, and re-injecting those stem cells. The patient is then capable of creating enough healthy red blood cells to treat the symptoms of their blood disorders.

As good as it is, CRISPR-Cas9 has limitations. The RNA guide molecule can sometimes be imprecise, leading to unintended cuts to a patient’s DNA. Moreover, because the tool breaks both strands in a DNA helix, the subsequent repair can also introduce unwanted insertions or deletions. Damage to genetic information like this could eventually lead to cancer or disrupt cellular function in other ways.

Updates to the technology are thus in the works. CRISPR-Cas9 nickases, for example, are enzymes that cut only one strand of the DNA double helix. To make genetic changes, nickases therefore need to be used in pairs, meaning less risk of off-target effects. It is unlikely that both nickases in an edit would bind incorrectly to the same section of DNA. Another method, “base editing”, can chemically change a single letter of a DNA’s sequence into another without the need for cuts.

Some of these techniques are already in the clinic. In 2022 a patient with familial hypercholesterolaemia was given an infusion of a base-editing treatment as part of a trial. The disorder, which affects one in 250 people, results in reduced clearance of bad cholesterol from the blood. The treatment, VERVE-101, made by Verve Therapeutics, turns off the PCSK9 gene in the liver by making a single-letter change in the DNA (from A to G).

Beam Therapeutics, based in Cambridge, Massachusetts, is using base editing to make therapies for a range of conditions. These include making four DNA-letter changes to immune cells so that they are better able to attack leukaemia, as well as a product that works for the same diseases as Casgevy. The company reckons its base-editing drug will work better than CRISPR-Cas9 and deliver higher levels of haemoglobin. Data from early trials of base-editing technology in patients are expected in the second half of this year.

At the clinical frontier is “prime editing”, which uses a Cas9 nickase along with a specially designed RNA guide that not only locates the correct region of DNA, but also carries a template of the desired change. Also attached to the CRISPR protein is an enzyme called reverse transcriptase. This reads the RNA template and synthesises the correct DNA sequence at the location of the nicked site, giving a precisely edited gene.

In April David Liu, a molecular biologist at Harvard University, posted on X that the first trial to use prime editing in a patient had been approved only four and a half years after his lab had published the first paper on the technology. Prime Medicine, a biotech firm in Cambridge, Massachusetts, has already begun clinical trials of its drug PM359 for the treatment of chronic granulomatous disease—a life-threatening condition that affects the blood’s ability to destroy infections.

Being able to change larger pieces of the genome, as is the case with prime editing, makes it possible to treat diseases where errors stretch over a long distance, like Huntington’s disease. But it could also help with the tricky economics of treating rare diseases. Instead of making a medicine that treats a single mutation to a gene, it would be possible to fix many types of mutation with one correction. The flexibility of the technology means that, in theory, prime editing could correct almost 90% of disease-causing genetic variations.

The technological progress in gene-editing tools has not stopped. Yet another method, known as “bridge RNA”, details of which were published in Nature in June, uses a form of guide RNA that recognises two stretches of DNA—the target site and the new gene that is to be inserted. This new technique allows large stretches of DNA to be added, removed or inverted.

All these new technologies face technical and safety hurdles in the years ahead. A big question is how to deliver therapies to the right place in the body. Blood cells, cancers, the retina and the liver are all easy to reach and edit. The brain and lungs are more difficult. One solution to the delivery problem, proposed by Aera Therapeutics of Cambridge, Massachusetts, is a capsid, a nanoparticle with a protein shell. Based on human proteins, these nanoparticles could be targeted to different tissues while also not provoking a strong response from the body’s immune system.

But perhaps the biggest challenge will be economic. So far, the new generation of genomic medicines have been eye-wateringly expensive—a shot of Hemgenix, a haemophilia B gene-therapy, costs $3.5m, around a million dollars more than Casgevy. Firms believe they can charge high prices not only because of the costs of developing and making the drugs, but because they offer potentially lifelong benefits (although the durability of these treatments remains to be proved).

There are reasons to think costs might come down in time. Treating diseases that affect larger patient groups, such as heart disease, would help reduce costs. Ultimately, many believe gene-editing tools will evolve into “platforms”, where the core technology would remain unchanged and only the specific instructions for changing genes would be tweaked for new diseases. This would reduce the need for clinical trials for every new drug. Until that happens, though, firms may be forced to drop even promising treatments because of market conditions. Yet gene editing is moving so fast that it seems only a question of when, not if, these new medicines will overcome their difficulties.

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