The Age of Crispr Medicine Is Here

The approval of the first Crispr-based therapy is just the beginning. Getting it to patients is the next hurdle.

Jimi Olaghere used to end up in the emergency room so often that the hospital reserved a bed for him. Sickle cell disease dominated his life. A genetic defect he was born with meant that instead of having flexible, round red blood cells like most people do, his were sticky and crescent-shaped. The cells clumped together, blocking blood flow and unleashing excruciating bouts of pain. He took painkillers to manage the episodes, but the drugs didn’t always help.

“It was a circus, bouncing from specialist to specialist and constantly desecrating my body with endless amounts of prescription pills, all in the hopes of finding a sliver of what it feels like to be alive,” Olaghere told an advisory committee to the US Food and Drug Administration in October.

When the opportunity came to participate in a clinical trial that would use Crispr gene editing in an attempt to permanently fix his disease, he didn’t hesitate. Now, more than three years after getting the one-time treatment, Olaghere is virtually pain-free. “My quality of life has soared to new heights,” he said during his testimony.

The therapy Olaghere received was approved in the UK on November 16, in the US on December 8, and in Europe on December 15 under the brand name Casgevy. It is the first publicly available medical treatment in the world to use Crispr technology. More are in the pipeline. The technology is poised to radically change the lives of patients with sickle cell—and eventually, many others.

“It’s the start of the era of Crispr medicine,” says Jennifer Doudna, a biochemist at the University of California, Berkeley, who shared the Nobel Prize in Chemistry in 2020 for her role in the development of the gene-editing technique. “I think it suggests that we’re on the edge of real transformation in medicine,” she says of Casgevy’s approval.

Doudna, along with Emmanuelle Charpentier, now of the Max Planck Unit for the Science of Pathogens in Germany, first described Crispr as a genome-editing system in the journal Science in June 2012. They extracted and simplified Crispr from the immune system of bacteria, which fight off attacking viruses by cutting up the invaders’ DNA.

The discovery changed science forever. Genome-editing tools such as zinc finger nucleases and TALENs (transcription activator-like effector nucleases) already existed, but Crispr proved to be far more efficient, not to mention easier and cheaper to use. Crispr can be used to knock out genes to investigate their function, but its real power lies in being able to change an organism’s DNA. Scientists have long imagined being able to correct defective genes to treat diseases at their source. Crispr offers a way to do that.

It took just over 11 years—lightning fast for drug-development timelines—for Crispr to move from a tool used in laboratories to a real therapy that could be prescribed to patients. “I’m very excited. I think this is an important milestone for the whole field,” says Feng Zhang, a biochemist at the Broad Institute of MIT and Harvard who, in January 2013, showed that it was possible to use Crispr to edit mouse and human cells in a dish.

Casgevy’s approval is proof that editing the code of life is not only possible, but also able to bring life-changing results for patients. But Crispr’s high sticker price and the complexities around administering it may limit its use for the foreseeable future. Casgevy will cost $2.2 million per patient in the US, and the therapy requires a lengthy hospital stay.

A Debilitating Disease

Sickle cell disease has been well understood for decades, making it a fitting first target for Crispr. Its cause, abnormal hemoglobin, was discovered in 1949 by chemist Linus Pauling. Hemoglobin is the protein in red blood cells that carries oxygen throughout the body. Pauling showed that hemoglobin has an altered chemical structure in people with sickle cell disease. It was the first time a disease was characterized at a molecular level.

In 1956, Vernon Ingram discovered that a single mutation in the HBB gene produces the abnormal hemoglobin. Everyone gets two copies of this gene, one from each parent. To have sickle cell disease, a person must inherit the mutated gene from both parents.

Abnormal hemoglobin alters the shape of red blood cells, turning them from discs to sickles. The misshapen cells stick together in vessels and cut off blood flow and oxygen, causing extreme pain. Sickled cells are also brittle and die more quickly than normal cells.

“The pain is far and away the worst part for patients,” says Alexis Thompson, a sickle cell expert and chief of the Division of Hematology at Children’s Hospital of Philadelphia. “They suffer from really debilitating pain.”

Over time, sickle cell damages organs and leads to early death. On average, patients with sickle cell disease in the US live to 52.6 years—more than two decades shorter than the rest of the population.

The first drug for sickle cell, hydroxyurea, wasn’t approved until 1998, and it was the only one on the market until 2017. Three more drugs have since become available to reduce pain crises, but they don’t help all patients.

The disease can be cured with a bone marrow transplant, which involves replacing a patient’s stem cells with healthy ones from a donor so that the patient can make normal red blood cells. But few get transplants, because they require a closely related donor and come with serious risks. After the procedure, the donor stem cells may attack the recipient’s body or fail to take over the role of producing new blood cells.

A Transformative Therapy

Casgevy, made by Crispr Therapeutics of Switzerland and Vertex Pharmaceuticals of Boston, doesn’t require a donor. It involves extracting a patient’s own stem cells from their bone marrow and editing them in a lab. The edited cells are then injected back into the patient. They travel to the bone marrow, where they take up residence and start producing healthy red blood cells.

Scientists don’t use Crispr to fix the mutated HBB gene directly. For all Crispr’s hype, it’s not good at replacing genes. But it is good at making targeted cuts in the genome. Casgevy targets a gene called BCL11A, which typically prevents the body from making a fetal version of hemoglobin. In the first several months of life, levels of fetal hemoglobin taper down and the body starts making adult hemoglobin instead. Making a cut in the gene releases the brakes, allowing cells to make the fetal type and override the abnormal adult kind.

In 1948, pediatrician Janet Watson noticed that children with sickle cell disease had normal blood cells as infants, but that the cells became sickled around six months. Scientists speculated that a fetal form of hemoglobin blocks the sickling process, but is turned off shortly after birth. They thought if they could figure out a way to switch on the production of fetal hemoglobin, they could override the mutation that causes sickle cell. The search took decades.

In the mid-2000s, research by Stuart Orkin’s lab at Boston Children’s Hospital found that switch: BCL11A. They first showed they could correct sickle cell disease in mice by knocking out the gene entirely. Then the group identified just a portion of the gene that could be inactivated and still turn on fetal hemoglobin—a safer approach, since genes often have many functions. In 2015, they showed that this stretch of DNA could be edited out with Crispr to boost fetal hemoglobin in mice and human cells.

Some people have a genetic condition in which they make fetal hemoglobin past infancy and are completely healthy. Crispr Therapeutics and Vertex used this insight to develop Casgevy. The companies launched a clinical trial in 2018. Of 31 patients who had multiple pain crises a year, 29 had none in the 12 months following treatment. “It is not an overstatement to say that gene therapy for this condition is transformational,” Thompson says.

For Olaghere, the treatment has given him the freedom to be a present father. And he’s now able to make long-term plans with his family, no longer worried about whether he’ll be stricken with another pain crisis. “Gene therapy has given me the ability to take full control of my life,” he told the FDA committee.

Who Will Get It?

Just how many patients will benefit from Casgevy remains to be seen. Sickle cell disease affects more than 100,000 people in the US, most of them of African and Caribbean descent. Adults and children 12 and older who experience recurrent pain crises are eligible to receive the therapy. Vertex says around 16,000 patients in the US and 2,000 patients in the UK may qualify.

But at $2.2 million, Casgevy is now one of the most expensive medicines in the world, and insurers have not yet said whether they’ll cover the cost of treatment. The Institute for Clinical and Economic Review, an independent nonprofit research institute in Boston, found that a price point of up to $2 million would be cost-effective considering the high lifetime costs of treating patients with severe sickle cell disease. In an email to WIRED, Heather Nichols, a spokesperson for Vertex, said the company launched a patient assistance program that connects patients and their caregivers to a care manager.

So far, only nine centers across the US are currently offering Casgevy, which may limit who gets access to it. Vertex says the number of participating sites will grow in the coming weeks and months.

And despite the promise of a pain-free future, the grueling process of getting Casgevy may be a deterrent for some.

Collecting stem cells from the blood can take hours, and multiple sessions may be needed to get enough cells to edit. After that is a harsh conditioning regimen. Patients must undergo chemotherapy to kill any lingering diseased cells and make room in the bone marrow for the newly edited ones. Chemotherapy can cause mouth sores, fatigue, hair loss, nausea, and other unpleasant side effects. It can also result in infertility. Vertex also plans to offer fertility support to commercially insured patients, but the benefit won’t extend to Medicaid recipients. In the US, freezing eggs and sperm can cost thousands of dollars, not to mention the cost of IVF.

Patients also need to be hospitalized for weeks while the edited cells make their way to the bone marrow and start making new blood cells. Olaghere spent a total of 17 weeks in the hospital to get Casgevy.

“I know there are going to be many patients who don’t go down this road because of fertility issues and the need to be in the hospital for a while,” says Sharl Azar, medical director of the Comprehensive Sickle Cell Disease Treatment Center at Massachusetts General Hospital, one of the initial centers to offer Casgevy. For those that do, he says resources such as housing, childcare, and food will be needed to help patients and their families. Nichols, the Vertex spokesperson, says the company will assist with travel and lodging and may help cover certain expenses such as hotels, transportation, and meals.

Sickle Cell and Beyond

Sickle cell may be the first disease to be treated with Crispr, but it won’t be the last. Researchers are setting the gene-editing tool against cancer, HIV, and other genetic diseases. But it can’t yet address every ailment.

For one, getting the Crispr system to the cells or organs you want to edit is still a challenge. By taking cells out of the body and editing them in the lab, Casgevy avoids this issue. But the approach is expensive, complex, and has limited uses. Another method uses an IV infusion to deliver Crispr in tiny bubbles called lipid nanoparticles that are taken up by the liver. But only some diseases can be treated this way. Ideally, Crispr would be given as an injection or even as a pill instead of a complicated cell transplant.

Newer forms of Crispr, including base editing, also promise to make more precise edits. With base editing, scientists can simply swap one DNA letter for another in order to correct a mutation or disable a gene. The first trial of a base-editing treatment is showing early hints that it may lower high cholesterol.

And Zhang, of the Broad Institute, recently used a search algorithm to discover hundreds of new Crispr systems hiding out in bacteria taken from breweries, Antarctic lakes, and even dog saliva. These new systems could be harnessed to edit human cells with even more accuracy.

Still, the long-term effects of Crispr remain unknown. Scientists hope gene editing is permanent, a one-and-done treatment. But they’ll have to follow patients for years to know for sure.

It’s why Azar is hesitant to call Crispr a cure. “We don't know what the long-term impacts are going to be,” he says. “We don't know what complication rates are going to look like, or whether this is going to have a mortality benefit or if this is going to truly stave off the life-threatening complications.”

Doudna is more optimistic. “I feel very excited about it. I think we have to be cautious, because it’s still the early days of Crispr, “ she told an audience at LiveWIRED in December. “But so far, it looks like people that receive this one-and-done treatment truly are cured of the effects of their disease.”

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