FOR 20 YEARS Tamani Harris lived a life of pain. She was born with sickle-cell disease. Her red blood cells, made flat and stiff by a mutant version of haemoglobin, struggled to move smoothly through her blood vessels. Several times a month she would have a “crisis” where her cells got stuck somewhere in her body, causing excruciating pain. She needed strong opioids and often blood transfusions to recover. She had accepted that she might die young.
Her parents encouraged her to partake in a trial for a CRISPR-based therapy for sickle-cell disease and beta-thalassemia, another debilitating genetic blood disorder. The therapy, Casgevy, was made by Vertex Pharmaceuticals, a pharmaceutical firm in Boston, and CRISPR Therapeutics, a Swiss biotech co-founded by Emmanuelle Charpentier, one of the inventors of CRISPR. In May 2021 Ms Harris travelled to New York from college in Florida to have her DNA edited.
Out with the old, in with the new
Sickle-cell disease can be treated by a bone-marrow transplant containing stem cells which lack the faulty haemoglobin gene and thus produce healthy red blood cells. But without a well-matched donor—and even siblings might not be similar enough—the transplant will fail or attack the recipient’s body. What Casgevy does is turn a patient’s own cells, already a perfect match, into a transplant. Doctors harvest stem cells from the patient’s bone marrow and then send them off to a lab, where CRISPR is used to turn up the production of another, functional version of haemoglobin. This version is used during fetal development but is turned down at birth. The patient—having had his or her old cells destroyed first by a brutal chemotherapy regime that often kills fertility—then receives their own edited cells as a transplant.
The treatment seems to have cured Ms Harris; she has not had a crisis in three years. It appears to have worked in 39 of 42 participants in her trial. The beta-thalassemia patients who received Casgevy have had a similar turnaround. In 2023 Casgevy became the first CRISPR treatment to win approval from regulators, first in Britain and then in America, and reach the clinic. It has a list price of $2.2m in America.
Casgevy delivers on CRISPR’s original promise that diseases can be genetically cured. In the late 2010s and early 2020s that promise spawned huge excitement and investment; gene-editing biotechs shot up, pulling in hundreds of millions of dollars despite having little clinical data. When the covid pandemic broke out, the idea that biotechnology was going to save the world only fuelled more hype.
Then interest rates spiked, dampening investor interest. And when the whole industry seized up CRISPR still had a lot to prove. Could it ever be anything other than a gruelling bone-marrow transplant? Would health-care systems pay the high price for a one-and-done cure? What was more, too many companies were going after the same diseases in the same ways.
Hard years followed. Companies discarded drugs for rare genetic diseases in favour of “high-value” diseases with more patients. One biotech firm, Editas, stopped work on its therapy against inherited retinal diseases despite good results in early trials, then shut down its successful programme for a rival to Casgevy. Prime Medicine, another biotech, slashed its pipeline from eighteen therapy programmes to five. Tome Biosciences, which had entered the field with more than $200m in funding, closed shop. It was a harsh reckoning. “So much for the Nobel prize-winning promise of CRISPR as a panacea,” says Fyodor Urnov, a geneticist at the University of California, Berkeley.
CRISPR has spawned new editors that can fix mutations
And yet. The fact that Casgevy works matters. So does the emergence of tools that can enable more precise edits than CRISPR. Base editing, invented in 2016 by David Liu at the Broad Institute in Massachusetts, in effect swaps out one base pair in DNA for another. Base editors first entered human trials in 2022, and preliminary data look promising. Prime editing, Dr Liu’s next invention, can rewrite anything from one base to whole sections of DNA by copying from a custom template. That began human trials in 2024.
And markets are being established. More than 50 people have begun the process to get Casgevy (not counting trial participants). That is only a tiny fraction of the 8m people with sickle-cell disease, but at current prices Vertex believes Casgevy to be a multibillion-dollar prospect. Analysts agree, citing public-payer deals in America and England and a coming expansion into the Middle East, which has a high prevalance of both sickle-cell disease and beta-thalassemia.
In vivo veritas
But for CRISPR to transform medicine it will have to expand beyond ruinously expensive cures for diseases that require gruelling bone-marrow transplants. It will need to cure ailments in gentler ways at lower costs. Sending away cells for editing is pricey. A number of companies are working on in vivo treatments, which work by doing all the editing inside the body rather than via transplant. These medicines would be cheaper and kinder on patients, and would allow companies to treat more common diseases. But it has been a challenge to deliver them to the right places in the body.
To attack this problem the field has bet heavily on lipid nanoparticles (LNPs). These tiny bubbles of fat, which are given as an infusion, proved they could be produced at scale when they delivered mRNA vaccines against covid. Each nanoparticle would contain both a CRISPR guidance system and an mRNA molecule that would produce the editing protein. Verve Therapeutics, a biotech firm in Cambridge, Massachusetts, has a nanoparticle-delivered base-editing system in clinical trials that would treat heart disease by silencing a cholesterol-regulating gene called PCSK9. The editor showed good early results, but the firm had to pause a trial in 2024 because one of the participants had an adverse reaction to the LNPs. Another trial with a different LNP formulation is under way.
If Verve can work out the kinks in delivery, the prize would be big. The LNP trial is aimed at treating premature coronary-artery disease and people with familial hypercholesterolemia, a genetic condition that affects millions globally, causing high cholesterol and a serious risk of atherosclerotic cardiovascular disease (ASCVD). But the company’s ultimate goal is to treat anyone with ASCVD—a patient pool of more than 300m people—and, one day, those merely at risk of it.
And if LNPs can be made to deliver editors safely, the next big leap would be making versions that could be delivered to organs besides the liver, where LNPs naturally accumulate (and which works for treating heart disease). If LNPs—or an alternative vehicle—could be made that could reach, say, the brain, gene editors could work on a host of brain diseases currently beyond the reach of CRISPR. Some researchers have turned to virus-like particles, which are capsules that exploit viral proteins to get taken up by cells but without a viral genome to cause infection. Jennifer Doudna, who co-invented CRISPR, is working on a version she calls “enveloped delivery vehicles”, which can be manufactured like LNPs but are decorated with molecules recognised by specific cell types.
Updates are expected in the first half of 2025 for trials run by Verve and by another Cambridge firm, Intellia Therapeutics, which has an in vivo therapy for hereditary angioedema, a swelling disease. Conditions for investment are also looking better. Interest rates are down. And America’s Food and Drug Administration (FDA) has agreed to lower its stringent regulation standards so that companies can re-use therapy components, such as editors or delivery vehicles, for different treatments without having to re-test them.
Dr Urnov welcomes the news from the FDA, but he is worried that for-profit companies have nonetheless abandoned people with rare genetic diseases. He fears that most of those potential patients will wait in vain for a biotech-developed treatment. To address this Dr Urnov, Dr Doudna and colleagues at the University of California in both San Francisco and Los Angeles have entered into a non-profit partnership with Danaher, a global conglomerate and a CRISPR manufacturer, in hopes of dosing patients with rare genetic diseases through a large, “umbrella”-style clinical trial. (It is not unlike personalised cancer-vaccine trials run by Merck, a pharmaceutical giant, where each vaccine is unique to the participant’s particular mutation.)
CRISPR is still a long way from becoming the standard of care for all genetic diseases, as Dr Doudna envisions. For some there may be better alternatives that do not rely on editing DNA, such as protein-targeting drugs for cystic fibrosis (for which CRISPR cures are also in development), or “antisense” therapeutics which can block the output of genes by binding to mRNA before it is translated into proteins. However, as scientists begin to understand more about how genetics underpin or shape all kinds of diseases both rare and common, the space in which CRISPR can be useful continues to grow. To take full advantage, gene-editing’s practitioners cannot afford to let up. ■