Gene-editing technologies for cancer and blood disorders are maturing a little more than a year after the first CRISPR drug was approved

CRISPR genome-editing grows up: advanced therapies head for the clinic

Gene-editing technologies for cancer and blood disorders are maturing a little more than a year after the first CRISPR drug was approved

A fresh wave of gene-editing therapies is surging to the fore — even as the field wrestles with the challenge of getting the first generation of expensive and complex CRISPR treatments to the people who need them.

Barely a year after the first government approval for a gene-editing therapy, researchers at the American Society of Hematology’s annual meeting in San Diego, California, presented data on gene-editing approaches for treating cancer and blood disorders, and for making stem-cell transplants safer. They also unveiled good news about the first approved treatment: benefits from the therapy, called Casgevy, can last for at least five years in people with either of two heritable blood disorders, sickle-cell disease and β-thalassaemia. Casgevy gained its first government approval little more than a year ago.

Casgevy had “a clear benefit in general health, physical, emotional, social and functional well-being,” said Franco Locatelli, a paediatric haematologist and oncologist at Bambino Gesù Children’s Hospital in Rome, who presented the data. The therapy, he added, has “the potential to provide a one-time functional cure”.

But although other companies are rushing to emulate Casgevy’s success, the treatment’s complexity and hefty price tag have raised concerns that it will be out of reach for many people.

Stuart Orkin, a paediatric haematologist and oncologist at the Harvard Stem Cell Institute in Cambridge, Massachusetts, said at the meeting, “The imperative now is development of effective and safe therapies that are readily accessible to the many patients who could benefit.”

Fetal form to the rescue

Both β-thalassaemia and sickle-cell disease are caused by mutations in one of the genes that code for haemoglobin, the oxygen-carrying molecule found in red blood cells. A different, fetal form of haemoglobin can help to compensate for the effects of these mutations, but its production is typically turned off shortly after birth. Casgevy uses CRISPR–Cas9 to disable that genetic off-switch, allowing fetal haemoglobin to be produced again.

Last November, the United Kingdom became the first country to approve Casgevy. The US Food and Drug Administration followed suit in December, and several other countries have since approved the therapy. More than 45 treatment centres around the world have been authorized to provide Casgevy, according to its developers, Vertex Pharmaceuticals in Boston, Massachusetts, and CRISPR Therapeutics in Zug, Switzerland.

But the treatment must be made from an individual’s own blood stem cells, a process that can take months. And countries are still grappling with how to incorporate the cost of the US$2.2-million therapy into their health-care budgets.

In the United Kingdom, for example, a government advisory body announced in August that the treatment would be made available through the nation’s health-care programme for up to 460 people with severe β-thalassaemia. But a decision is still pending on whether Casgevy will be provided to people with sickle-cell disease; that usage may not be cost-effective, the advisory body said in March.

That prompted an outpouring of dismay from the public, says Yasmin Sheikh, head of policy and public affairs at Anthony Nolan, a charity in London that is focused on blood cancers and blood stem-cell transplants. The charity was inundated with letters and calls. “We had more responses than we’ve ever had to any medicine appraisal before,” Sheikh says. “It was powerful, and it was sad.”

Durable benefits

One of the advisory body’s concerns was uncertainty about how long the effects of Casgevy will persist. At the haematology meeting in San Diego, researchers presented data showing that the benefits can last for at least five years for both sickle-cell disease and β-thalassaemia. Treatment with Casgevy reduced the need for blood transfusions in people with β-thalassaemia and for hospitalizations in people with sickle-cell disease. More than 90% of participants with sickle-cell disease reported that they had had no pain crises for at least 12 consecutive months — excruciating episodes caused when misshapen blood cells block blood vessels.

It’s a proof-of-principle for gene-editing therapies that has buoyed a host of other companies and academic researchers in the field. At the meeting, Justin Eyquem, a cancer immunologist at the University of California, San Francisco, presented the results of animal experiments that used CRISPR–Cas9 editing to engineer cancer-fighting immune cells called CAR T cells. And Paula Rio, an immunologist at the Autonomous University of Madrid, discussed how she is testing several gene-editing techniques to design a therapy for Fanconi anaemia, a rare genetic disease that raises cancer risk.

Others are sticking with sickle-cell disease. Beam Therapeutics in Cambridge, Massachusetts, presented data from its first clinical trial of a sickle-cell disease treatment that uses a technology called base editing. This method is related to CRISPR but makes more-precise changes to DNA than CRISPR does. Fetal haemoglobin levels rose to comprise more than 60% of total haemoglobin in the seven people who had been treated by late October.

Life-threatening risks

Such therapies, including Casgevy, come with risks: the death of one participant in the Beam clinical trial was probably the result of a chemotherapy treatment used to eradicate unedited blood stem cells from the body, a process necessary to make room for the edited cells to flourish. This chemotherapy, called busulfan, can also cause infertility.

At the meeting, Beam and another Cambridge-based gene-editing company called Prime Medicine presented results from experiments in animals that had tested ways to make this process safer. Beam used an antibody that specifically targets blood stem cells, reducing their numbers, but leaving other cells unharmed. The company then altered its base-editing therapy to make the edited cells immune to treatment with the antibody. Studies in animals suggested that the approach could work: edited cells persisted in treated animals for at least six months.

Prime Medicine presented data from a similar approach to avoiding chemotherapy using a newer editing technique called prime editing. Prime editing can insert or delete DNA with more precision than CRISPR–Cas9 editing can and is more versatile than base editing.

Overall, these approaches and others could be crucial to making gene-editing treatments for blood disorders safer and more accessible, John Tisdale, a haematologist at the National Heart, Lung, and Blood Institute in Bethesda, Maryland, said at the meeting. “The way we’re doing it now is just not scalable,” he added. “But things are moving quickly.”

doi: https://doi.org/10.1038/d41586-024-04102-w

This story originally appeared on: Nature - Author:Heidi Ledford