With CRISPR cures on horizon, sickle cell patients ask hard questions about who can access them

LONDON — Victoria Gray had come to Nashville, Tenn., from her home in Mississippi for what was supposed to be a routine checkup. But when a pain crisis struck — an agonizing emergency of sickle cell disease in which Gray’s misshapen red blood cells caught in her blood vessels — the visit became a days-long hospital stay.

It was in the midst of this attack that her doctor told her about a clinical trial for a new kind of treatment, one where CRISPR would be used to alter her blood cells’ DNA, boosting their ability to produce healthy forms of oxygen-carrying hemoglobin and, hopefully, preventing them from deforming and wracking her body with pain. She was warned it had never been done before, and there could be complications. She went home, thought and prayed on it. And in the end, she decided to do it for her family — her husband and four children.

“I wanted to be able to dress my daughters for their weddings, be there when they sign up for college, and just experience life with them,” Gray told reporters at the Third International Summit on Human Genome Editing in London this week. The crippling pain she’d endured since she was a child wasn’t really a life, she said, just an existence. “I felt that I had nothing to lose, I was at the end.”

Now, at age 37, free of symptoms, able to be a mom and work a full-time job, Gray is able to “dream again without limitations,” she said on stage at the summit. Her story represents a triumph of CRISPR gene editing, a field of science barely a decade old.  It also shines as a beacon of hope to the millions of people around the world living with sickle cell disease — a disorder long subjected to scientific neglect and medical racism. But the fast-approaching reality of a one-time cure for the disease is also forcing the gene-editing world to grapple with tough questions of equity and access.

The thorny question at the heart of two days of discussion: How to prevent this technology from falling into the same traps as every other one that’s come before.

Summit speakers emphasized that technological innovations in engineering and manufacturing aren’t going to be sufficient. Innovation in pricing, payment, and intellectual property will have to be part of the answer too. “It really feels like we need to have a rethink,” said Claire Booth of University College London, in order “to achieve sustainable and affordable access to life-changing gene therapies.”

Gray is the first person to have received a CRISPR-based therapy for sickle cell disease, developed jointly by CRISPR Therapeutics and Vertex Pharmaceuticals. Since her infusion in July 2019, more than 75 other patients have received the same experimental treatment or similar ones being developed by other companies.

Results so far have brimmed with promise. Clinical trial participants who received the one-time treatment developed by CRISPR/Vertex have remained free of the agonizing symptoms caused by misshapen blood cells for months — some, like Gray, for years. Many more people may soon reap these same benefits.

By the end of this month, CRISPR Therapeutics and Vertex are expected to file approval paperwork with the U.S. Food and Drug Administration. If given the green light, it would be the first marketed therapy based on the Nobel Prize-winning CRISPR technology.

It’s a moment that one summit speaker, Alexis Thompson of the University of Pennsylvania and Children’s Hospital of Philadelphia, likened to a turning point in the American civil rights movement. “We are now faced with the fact that tomorrow is today,” she said, quoting an anti-Vietnam war speech that Martin Luther King Jr. delivered at Riverside Church in April 1967, exactly one year before he was assassinated. “Many of us always thought of gene editing as being tomorrow, but in fact tomorrow is today.”

The companies have not disclosed a projected price tag for the one-time treatment. But it’s not unreasonable to imagine a cost that mirrors the $4 million to $6 million a single sickle cell patient in the U.S. accrues over a lifetime of drugs, infusions, and hospital visits. Other licensed gene therapies, like Novartis’s Zolgensma for spinal muscular dystrophy and Bluebird bio’s Zynteglo for beta-thalassemia, cost $2.1 million and $2.8 million, respectively.

Cost is a huge barrier for getting treatments to the places in the world where the vast majority of sickle cell patients live, namely countries in sub-Saharan Africa. But there are other barriers as well. All of the CRISPR-based therapies currently in clinical trials are what’s called ex vivo, meaning they require bone marrow cells to be collected from patients, edited outside the body, and then infused back. It’s an involved procedure, requiring a bone marrow transplant and chemotherapy conditioning beforehand to make room for the edited cells to engraft.

In the U.S., there are approximately 200 specialized centers for bone marrow transplants. There are only three such centers for all of sub-Saharan Africa — in Nigeria, Tanzania, and South Africa. Making these types of CRISPR-based therapies available throughout the continent will require massive investment in clinical infrastructure.

“The road from now, having gene editing that is possible and implemented where most people live, it’s not that close,” said Ambroise Wonkam, a geneticist at Johns Hopkins School of Medicine and the University of Cape Town who also serves as president of the African Society of Human Genetics. “We have to put that into perspective.”

An alternative approach that has begun to gain traction as a potential solution is in vivo therapies, where gene-editing components would be injected into a patient’s body directly. That would eliminate the need for a transplant procedure and the chemotherapy that accompanies it. Investments in that approach might bring down the cost of a single dose from $100,000-$500,000 to $1,000-$2,000 in low- and middle-income countries over ten years, according to projections presented by Emily Turner of The Gates Foundation.

Over the last four years, the Gates Foundation and the National Institutes of Health have jointly invested $200 million in developing low-cost gene therapies for sickle cell disease and HIV focused on in vivo approaches. But these present their own engineering challenges. Getting large numbers of CRISPR components into the right blood cells, which reside in the bone marrow and are protected by a cadre of other immune cells, is a significant scientific hurdle.

Whatever the tradeoffs, patients urged the room to consider them, and to consider them with urgency. Because while tomorrow may be here now for individuals in wealthy countries like the U.S. and the U.K., people in countries that bear the highest sickle cell disease burden are still being left in the past.

“The Tanzanian sickle cell community is ready for new therapies,” said Arafa Salim Said, who has used her own experience with sickle cell to build Tanzania’s first patient advocacy organization. But therapies have to be affordable and fit into the challenges of patients’ daily lives. “A new therapy can be extremely effective, even a cure for sickle cell, but if it’s not made accessible to the average patient, it won’t be used.”

Take hydroxyurea, an oral drug that makes red blood cells more flexible, reducing pain crises and the need for blood transfusions. It was first approved by the FDA in 1998, and has helped improve the lives of thousands of American patients. Sickle cell is still a terrible disease, but the drugs allow most people to reach adulthood. In Tanzania and other African nations, however, hydroxyurea has only become available in the past few years. With the lack of treatments and other healthcare challenges, 50-90% of babies born in Africa with sickle cell disease do not live to see their fifth birthday.

In India, which has the second-highest rate of sickle-cell prevalence in the world, hydroxyurea is often difficult to access, said Gautam Dongre, secretary of India’s first national sickle cell patient advocacy group, whose two children suffer from the disease. If after 40 years, that drug still has not reached many people in India, particularly those living in remote areas, he said, “then what about gene therapy?”

For an event that has historically been primarily focused on the science of gene editing, it was powerful to instead have the world’s leading experts reflecting on and responding to these questions of equity, access, and medical justice, Julie Makani of Muhimbili University of Health and Allied Sciences and a member of the Summit Organizing Committee told STAT in an interview. But there was one question that she and others posed that never received an adequate response: When are clinical trials of gene therapies for sickle cell going to be conducted in Africa?

That’s a goal Makani has been working toward in Tanzania for the past five years. “We keep hearing the same reasons why it can’t be done—cost and infrastructure—but we know those are issues we can address.”

Makani also helped lead an ambitious effort to train a new generation of African scientists in genomic science while conducting population health research. Called H3Africa, it launched a decade ago, and has since produced hundreds of publications detailing new connections between genes, health, and disease. She pointed out that it’s only in the last few years that research centers in the U.S. and Europe have built the necessary capacity to run the bevy of sickle cell gene therapy trials now underway.

“Everyone is learning,” she said. “And we have patients who are ready to participate and right now the only option is to send them abroad. But we believe there is much we can contribute to the generation of data and knowledge if given the opportunity and the resources to do so.”