CRISPR could end sickle cell disease, but signing up black patients for clinical trials will be a hard sell
he first attempts to use a groundbreaking gene-editing technology in people will likely target patients with sickle cell disease, a crippling inherited disorder that in the U.S. predominantly strikes African-Americans.
That should be welcome news, after decades of sickle cell patients being neglected by the health care system, scientists, and drug companies. But the long and ugly history of unethical experimentation and mistreatment of black patients could make recruiting volunteers to try largely untested CRISPR therapies a tough sell.
“You can’t expect this population is just going to stick out their arm for an IV,” said Mary Brown, who heads the Sickle Cell Disease Foundation of California and has worked with patients for four decades. “There’s a lot of education that needs to be done. I don’t want to say hand-holding, but that’s what it is.”
Brown had just come from the funeral of a 37-year-old man with sickle cell she’d known since he was 4. “This is a disease where people have not taken any time, where people have been treated with no sense of empathy. Those kinds of things don’t make you trust the system.”
Clinical trials of sickle cell treatments that use CRISPR could start as soon as this year, and some scientists leading those efforts are beginning to lay the groundwork. They are meeting with leaders of black churches and creating teaching guides for pastors, and one NIH researcher is surveying sickle cell patients and their parents to assess what fears they may have about CRISPR, or if they’ve even heard of it. But many scientists say they’ve been so busy working on the science, and safety, of the therapies that they haven’t yet done the outreach they know is urgently needed.
People like Andre Harris will be hard to persuade. “To me, the risk greatly overshadows the benefits,” said the 28-year-old social work student from Fayetteville, Ark. He has suffered strokes, surgeries, blood transfusions, and the loss of his gallbladder since being diagnosed with sickle cell before birth, but said he’d have to be more desperately sick to sign up.
Nurses and doctors, Harris said, have accused him of “being a drug seeker” when he’s sought relief from the excruciating pain the disease can cause when blood vessels are blocked. “I do not like to play what we call the race card, but if you pay attention to history, you see a lot of medical racism,” he said.
He is excited about the potential of the therapies — which promise to reduce symptoms or even cure the disease — and knows some patients do have to be the first to test them. Still, he said signing up people from a medically disenfranchised African-American population may prove more difficult than researchers realize.
Dr. Mark Walters, part of a University of California-led team working on one CRISPR-based therapy, understands the distrust among patients like Harris. The country’s most common genetic disorder, sickle cell affects some 100,000 people in the United States — causing severe pain, stroke, organ failure and premature death. Yet the FDA has approved only two drugs to treat these symptoms.
“You can’t expect this population is just going to stick out their arm for an IV.”
Mary Brown, Sickle Cell Disease Foundation of California
In contrast, hemophilia, a disease that affects 20,000 Americans — mostly white males — has an arsenal of about 30 approved drugs, noted Walters, who is also a hematologist at UCSF Benioff Children’s Hospital Oakland: “It’s shocking, isn’t it?”
So Walters is thrilled that sickle cell disease “is going to be the one we’re going to fix first” with a CRISPR-based treatment. “It’s groundbreaking work,” he said. “Why shouldn’t African-Americans be the first to benefit?”
Many African-Americans remain deeply wounded by the infamous Tuskegee study — experiments in which the U.S. Public Health Service misled hundreds of black men they’d recruited for a syphilis study and allowed many to go untreated for decades. The project was stopped amid public outcry in 1972, but left a legacy that continues to this day: African-Americans have a dismally low turnout for clinical trials.
“We know most clinical trials suffer from Tuskegee syndrome,” Harris said. “People think the government is out to get them. Well, at one point, the government was out to get them.”
The reservoir of anger and suspicion left by the Tuskegee study can be hard to shake, even for those with extensive scientific credentials, like Tshaka Cunningham. He earned a bachelor’s degree in molecular biology from Princeton University and a Ph.D. from Rockefeller University, and he did postdoctoral training at both the Pasteur Institute in Paris and the National Institutes of Health.
“Tuskegee left a psychological scar for many African-Americans, myself included,” Cunningham said. “It took me a long time to work through it.”
He now works at a nonprofit that seeks to improve health care. But he previously worked at the Department of Veterans Affairs, where he saw firsthand the reluctance of African-Americans to participate not only in clinical trials but also in genetic research. A study conducted before the launch of the Million Veteran Program, which seeks to study how genes influence health, showed that while 72 percent of Caucasians and 82 percent of Latinos were likely to participate, the number dropped to 50 percent among African-Americans.
“Some of my colleagues said, ‘We don’t understand this big drop-off,’” Cunningham said. “I’m like, ‘I do.’ It’s the whole accumulation of things, from Henrietta Lacks to a whole series of negative interactions with the medical community.” (Lacks is an African-American woman whose cancer cells were taken without her consent to create one of the most important cell lines in medical research.)
A 2016 analysis of thousands of genomic studies showed what researchers called “persistent bias:” 81 percent of participants had European ancestry, while people with African, Latin, or indigenous ancestry totaled less than 4 percent.
This lack of buy-in means African-Americans could be left behind as new genetic therapies are developed. “If people don’t avail themselves of these benefits because of the past,” Cunningham said, “then they are letting the evil win twice.”
He sees a need for “honest brokers” — African-Americans like himself who are scientists or clinicians and trusted by their communities — to build bridges between researchers and patients who may benefit from CRISPR-based therapies. But people like Cunningham are few and far between.
“Often I’m either the only African-American or one of few scientists of color in the room,” he said. “This needs to change.”
For now, Cunningham and others are looking to grassroots organizations for help, to advocacy organizations that support sickle cell patients, and to churches. While faith and science are often seen as in opposition, Cunningham, an ordained Baptist deacon, said black churches have a long history of health ministry, holding free clinics, blood drives, and prostate cancer screenings, for example.
Cunningham is helping to create a curriculum so pastors can be educated about CRISPR and other new medical technologies before they start receiving questions from parishioners. “I often quote the Book of Hosea, ‘My people are destroyed for lack of knowledge,’” Cunningham said. “Well, this is knowledge we can’t afford to lack.”
Earlier this month, ministers and researchers came together at a conference in Berkeley to discuss why minorities are being left out of precision medicine and how best to draw them in. (The conference was supported in part by Caribou Sciences Inc., a company co-founded by CRISPR pioneer Jennifer Doudna of UC Berkeley.)
The “Freedom with CRISPR” gathering was an eye-opener for Mark A. Dewitt. A project manager at UC Berkeley and the University of California, San Francisco’s Innovative Genomics Institute, he was first author on a 2016 paper showing that CRISPR could be used to correct the sickle cell mutation in blood stem cells taken from patients and that those corrected cells could survive for months after being transplanted into mice. With $4 million from the California Institute of Regenerative Medicine, Dewitt is part of a team hoping to ready the therapy for clinical trials in the next few years.
Dewitt’s focus right now is on safety. He wants to make sure the CRISPR edits have no off-target effects that could cause dangerous changes in other parts of the genome, that the genetic editing tools he’s using don’t cause immune reactions, and that corrected blood stem cells “stay stemmy” so they continue to produce all the types of cells a healthy body needs. But spending two days with faith leaders, he said, made him realize that his team needs to start early to get out the word about CRISPR clinical trials and must engage potential volunteers in a dialogue.
“It has to be a conversation every step of the way,” he said. “It can’t be patronizing. It shouldn’t be coming from on high.”
As soon as he started hearing scientists talk about using CRISPR as a therapy for sickle cell, Vence Bonham Jr., an associate investigator in the social and behavioral research branch of NIH’s National Human Genome Research Institute, thought it would be critical to find out whether patients would embrace the therapy or remain leery.
This summer, he had groups of patients, parents, and physicians learn about CRISPR, take part in focus groups, and take surveys to gauge both their hopes and concerns. Bonham is now analyzing data from the study and plans to publish the results soon.
“Clearly there is a lot of hope and a lot of interest, but there is also a lot of wariness about how it will be implemented,” Bonham said. One issue that surfaced repeatedly, he said, was cost. “There’s a concern this will benefit only a few,” he said.
One of the first companies to sell a CRISPR therapy for sickle cell disease may be Switzerland-based CRISPR Therapeutics, which has filed an application with the Food and Drug Administration to begin clinical trials. “Our goal is to dose a patient this year,” said CEO Samarth Kulkarni. The company’s approach is not to correct the sickle mutation, but to edit a patient’s stem cells so they produce more fetal hemoglobin, which can reduce the severity of the disease.
Kulkarni said his company hasn’t started working on outreach strategies yet, but he believes patients will be eager for new treatment options. “Our sense is that patients will welcome something that can really help,” he said.
He said it was far too early to think about pricing but said an effective treatment could save the health care system money. “The cost of caring for sickle cell patients can be hundreds of thousands a year,” he said.
Dr. Matthew Porteus, an associate professor at Stanford Medical School and one of the scientific founders of CRISPR Therapeutics, said that in his own lab, he is pushing, like the Berkeley team, to fully correct the sickle mutation — an approach that may work for other blood diseases as well. Aided by $5.2 from CIRM, Porteus hopes to start clinical trials next year.
“We recognize it’s an aggressive timeline, but we feel like we should be pushing ourselves,” he said. Porteus said it was also time to engage with patients, families, and advocacy groups: “We can’t be scientists and researchers in an ivory tower.”
“It has to be a conversation every step of the way. It can’t be patronizing. It shouldn’t be coming from on high.”
Mark A. Dewitt, University of California, San Francisco’s Innovative Genomics Institute
Hematologist Walters said he and other researchers have useful experience from years of recruiting sickle cell patients for stem cell transplants. “It’s quite an extensive process to get a family ready to participate,” he said, “It’s not done quickly in a one-hour session, I can tell you that.”
He said he wants to make sure any therapy he tests has as few risks as possible before it’s offered. Researchers are mindful that deaths in gene therapy trials in the ’90s halted work in the field for years. They are also mindful of the courage required by participants.
Among clinicians, there is concern that sickle cell patients seeking cures be realistic about when biotech may deliver. Dr. Lewis Hsu, a pediatric hematologist at the University of Illinois Hospital in Chicago, is excited about all the research in the sickle cell space and new drugs in the pipeline; he’s actively researching a number of them.
But he is not holding his breath for CRISPR cures just yet. “I’ve been in this field for 24 years and gene therapy has always been on the horizon,” said Hsu, who has written a guide for sickle cell patients and serves as vice chief medical officer of the Sickle Cell Disease Association of America. “We know it’s not easy.”
Yet the glaring need for new treatments is clear. Shakir Cannon, a sickle cell patient and advocate from Albany, N.Y., co-founded the Minority Coalition for Precision Medicine to encourage participation in genetic studies; the Berkeley conference to link the research and faith communities was his brainchild. Cannon hoped, he wrote recently, that CRISPR therapies would not only help cure sickle cell disease, but could also “offer a small step towards mending a shattered relationship” between biomedical and African-American communities.
In December, though, less than two months before the conference, Cannon died of complications from sickle cell disease. He was 34.
Published at Wed, 21 Feb 2018 09:35:31 +0000