How gene therapy is helping children with this devastating disease.
By Joy Harrington, Writer
When Mr. and Mrs. Jones married and left their homes in South Carolina for New York, they did not know that they each carried with them a gene for a blood disorder known as sickle cell disease. Two of their six children—Louis and Mildred—each received two copies of the defective hemoglobin gene, one from their father and one from their mother, which meant they both had sickle cell disease. But neither parent knew it.
Louis and Mildred could not move and play like their four siblings or the other children in their Queens neighborhood. They tired easily, due to their persistent, but unexplained, anemia. Pain with no apparent cause plagued them and nothing eased it.
In 1963, when he was 5, Louis was hospitalized with a high fever, indicating a severe infection. The pain was so intense he could hardly speak. His parents and his doctors did not know what was wrong. It was the first of many times he’d spend in the hospital throughout his life.
Then, in 1972, Mildred’s kidneys unexpectedly failed. Finally, a doctor tested the family for the defective hemoglobin gene that causes red blood cells to stiffen and hook, making it very difficult for them to flow through blood vessels and carry oxygen to the body’s cells. Sickle cell disease causes excruciating pain episodes, medically known as vaso occlusive crises, and damages organs, often leading to liver, heart, or kidney failure.
Louis Jones was 12 years old and his sister Mildred was 13 when they were finally diagnosed with the genetic disorder. Mildred would spend 17 years of her life on dialysis due to sickle cell disease. She died at the age of 30.
For years in the United States, children born with sickle cell disease rarely survived to be teenagers. Today, virtually all children with sickle cell disease live into adulthood, but the disease takes a heavy toll.
That may be about to change. Bone marrow transplants and experimental gene therapy are curing the disease. If the gene therapy works long-term, sickle cell disease would be the first genetic illness ever cured by altering genes. A cure would free children and young adults from lifetimes of pain, organ damage, and the erosion of their bodies and quality of life. But for the people who have already beat the odds and survived to middle age and beyond, the good news might be coming too late. Curing people like Mr. Jones will not repair the damage done to their bodies by sickle cell disease.

Painful and deadly

Normally, the red blood cells in our bodies are soft and doughnut-shaped. The protein hemoglobin—which gives blood its red color—carries vital oxygen to all the cells in the body as red blood cells flow easily through the largest blood vessels. Sickle cell disease gets its name from the shape of its characteristic blood cells, resulting from a single gene mutation that deforms the hemoglobin. Instead of soft doughnuts, the red blood cells are stiff and crescent shaped.
These sickled red blood cells do not carry oxygen well, if at all, and they do not flow easily through the blood vessels. They can get stuck in the tiniest blood vessels, blocking the flow of healthy blood cells and causing organ damage, even strokes, by depriving tissue of needed oxygen. The blockages can cause excruciating “pain crises,” when the patient is so overwhelmed with pain they may have no choice but to be hospitalized.
There’s the pain and then there is the litany of harm the sickled blood cells wreak on the body. The body destroys sickled red blood cells faster than it can create healthy cells. This renders sickle cell disease patients persistently anemic. People with sickle cell can also suffer from acute chest syndrome—a condition that can lead to the death of lung tissue due to lack of blood supply—to frequent infections, leg ulcers, even vision and hearing loss. Sickle cell patients can die from strokes caused by the illness. The leading cause of death for patients with sickle cell disease is bacterial infections, such as pneumonia, due to how badly the illness can weaken the immune system. Sickle cell disease can also lead to fatal liver, kidney, or heart failure.
In sub Saharan Africa, where the majority of the world’s children with the disease are born, most die before their 5th birthday. In the U.S., mandatory newborn screening beginning in the 1970s, the pneumonia vaccine, and routine blood transfusions have made a dramatic difference in life expectancy. Today, the average life expectancy for a person with sickle cell disease is 50 years, though they can live longer depending on the severity of their illness.
“When I was 40, the doctors told me I wouldn’t live much longer,” Louis Jones says. “They said the same thing when I turned 50.”
Jones is 61 today. In his Queens apartment, he glides through his living room before lifting himself out of his wheelchair to his couch. The room is warm. He doesn’t let the temperature go below 70 degrees, at any time of year, because catching a chill can trigger a pain crisis.
It’s hard to describe the intensity of the pain, Jones says. The oxycodone he takes usually just dampens it, makes it tolerable. It’s better than the aspirin he used to take in his youth, when there were no drugs available to treat the illness or the pain. He missed school often. He spent weeks in the hospital. “I was always behind, playing catch up,” he says.
Everything he learned about his illness, he taught himself. He was 20 when he realized that simply swimming in cold water, which causes blood vessels to constrict, could trigger a crisis that would land him in the hospital for a week or more. But he discovered that the fitter he stayed, the fewer pain crises he would have. He started his own landscaping business, combining his love of the outdoors with his desire for physical activity. He enjoyed it, but it was hard. “If I had a crisis, I might have to go on disability for a while,” he remembers. Besides aspirin, he took folic acid supplements to help spur the development of new, healthy red blood cells. Doctors, he says, were little help back then.
“Doctors used me as a guinea pig,” he says. “They didn’t know anything about sickle cell. They learned from me.”

Misunderstood, mistreated

Sickle cell disease is the most common inherited blood disorder in the world. More than 100,000 people live with the illness in the U.S. alone. As many as 10% of all African Americans carry the sickle cell disease gene. And yet, adults living with sickle cell disease frequently report encountering doctors who don’t know anything about it and don’t know how to treat it.
Marcus Brogdon-Simmons, 39, of Queens is a husband and a stay-at-home father who lives with sickle cell disease. With his crises, the pain emerges in his lower back then spreads down his legs as it intensifies. “It’s like a laser, a concentrated heat beam,” he explains. “It’s really horrible.”

Years ago, he sought care for his sickle cell disease in hematology clinics specifically designed for people with blood-related illnesses, but the clinics were filled with cancer patients who took precedence over him. If he wound up in the emergency room due to a pain crisis, he could sit for hours. “I’d watch people with toothaches, cuts, and scrapes get treated and released before a doctor even saw me,” he says.
When he finally saw doctors, it was likely they never even heard of sickle cell disease. “They’d ask if you can touch the pain,” he says, “No. It’s not muscular. It’s much deeper.”
Sickle cell patients often report waiting for long periods in emergency rooms without seeing a doctor for many reasons, including that they don’t look like there is anything wrong and doctors simply don’t believe they are in as much pain as they say. Race is a documented factor in this mistreatment. Studies have shown that doctors actually believe black people can tolerate more pain than people of other races. It’s also been shown that sickle cell disease patients seeking treatment frequently encounter doctors who won’t treat them or won’t treat them adequately because the doctors believe they are addicts seeking drugs.
Brogdon-Simmons has experienced that first hand with emergency room doctors. “They think I’m drug seeking,” he says. “It’s embarrassing. I’m in pain and being accused of faking it to get high.”

Sickle cell pain is notoriously difficult to treat, particularly in adults. Brogdon-Simmons takes extended-release morphine for his chronic pain and 8 mg of Dilaudid, an opioid, for acute, excessive pain that usually heralds the onset of a pain crisis. Consider that a typical dose of Dilaudid for a cancer patient is 4 mg. The first time Brogdon-Simmons took Dilaudid was shortly after his first child was born. It was Christmastime. He’d been fighting through pain, trying to enjoy the holiday with his newly expanded family. He could not endure it, however, and was hospitalized for two weeks. There, he was given the powerful drug in an IV drip. It took his pain from 10 on the self-reported pain scale to 7. Only 7. Morphine drips, on the other hand, would only decrease his pain to a 9, he says.
“I don’t think people believe it’s as painful as we say,” Brogdon-Simmons says. “I’ve heard people say it couldn’t be worse than childbirth. But I explained that childbirth eventually ends, you have the baby. With sickle cell disease, it’s consistent. Sickle cell pain doesn’t end.”

Treating sickle cell

Dr. Ilene Friedman knows. She’s the physician who has been running the adult sickle cell disease clinic at Northwell Health’s Long Island Jewish Medical Center for the last seven years. She has learned what works, including regular blood transfusions and hydration through IV drip. Treating pain, though, is top of the list. “They really need help,” she says of her patients.

Brogdon-Simmons now gets his regular care in Friedman’s clinic. “She’s something else,” he says. “She’s the best.”
Her patients text her directly to ask questions or tell her how they’re doing. More than 200 patients rely on the clinic for their routine medical care, blood transfusions, and pain management.
“Our mission is to get our patients out of the hospital and out there living their lives,” she says. “When they’re stuck in the hospital, they’re in pain. They lose their jobs. They miss their kids growing up.”
She easily recalls past and current patients and the details of their lives. A young woman had a stroke due to sickle cell disease, forcing her to deliver her baby prematurely at 27 weeks via C-section. The baby survived, is perfectly healthy and will turn 3. The mother gets monthly blood transfusions as part of her care.
Then there’s the 30-year-old woman who has had both hips and shoulders replaced because of the joint damage done by sickle cell disease. When she came to the clinic, Friedman put her on hydroxyurea—long the only drug approved specifically to prevent pain crises—opioids, anti-inflammatory medicines, even acupuncture and physical therapy. With intensified care, the young woman was able to return to work.
“This disease affects every body system,” Friedman says. “It not just pain. The fact that they can live their lives, have children, go to school, go to work, is practically heroic.”

Cure is costly

After decades with no advancements in treatment, suddenly sickle cell disease is on the brink of a cure thanks to the evolution of gene therapy.
“Our hope is that in the next five to ten years, that gene therapy is proven effective,” says Banu Aygun, associate chief of hematology and the sickle cell disease section head at Northwell’s Cohen Children’s Medical Center in New Hyde Park, NY. The Cohen clinic provides care for more than 500 pediatric sickle cell disease patients.

“The dream is that every child diagnosed with sickle cell disease would be cured with gene therapy right at the beginning,” Aygun says.
Bone marrow transplants, for now, are the only way to cure the disease but they are expensive and come with substantial risks. Patients undergo a course of chemotherapy to kill their own bone marrow before they can be infused with healthy donor marrow. Some sickle cell disease patients, including adults who’ve sustained significant organ damage or illness, aren’t healthy enough for the process. The procedure is most likely to be successful if the matching marrow donor is a sibling free of the disease. In a clinical trial conducted by researchers from the National Institutes of Health, bone marrow transplant cured all but four of 30 patients with severe sickle cell disease.
The procedure is not without risk. The chemotherapy to prepare for transplantation can be toxic, particularly for patients who’ve already sustained organ damage. Bone marrow recipients can contract graft vs. host disease where immune cells in the donated marrow attack cells in the recipient’s body. Friedman lost a patient to graft vs. host disease after a bone marrow transplant. The young woman was 21 years old and suffered from transient ischemic attack, or mini-strokes, caused by sickle cell disease. She was a candidate for a bone marrow transplant and proceeded with the treatment, but contracted the illness. She suffered for six months, Friedman says. “It was a slow, awful thing to watch her die.”

The promise of gene therapy

New gene therapy should solve some of the problems caused by bone marrow transplants. For one thing, a patient wouldn’t need a donor and therefore would not need immunosuppressants or risk graft vs. host disease, Aygun explains. Instead, a normal hemoglobin gene is introduced into the patient’s own marrow cells in a lab, then reinfused into the body. Once the new marrow replaces the old marrow, the sickled cells (and the disease) disappear.
As with donated bone marrow transplants, the patient undergoing gene therapy would still have to undergo a course of chemotherapy to destroy their bone marrow. The procedure is still experimental and it’s not clear yet if the cure is permanent. The first recipient has been disease-free for just three years.
Despite the real risks, these interventions are the future of sickle cell disease treatment. If they work, as Aygun and many others hope, they can cure people before the disease has an opportunity to cause irreparable damage.

Better treatments coming

Louis Jones’ sickle cell disease was relentless. It destroyed the blood vessels of his eyes and he lost his sight. It destroyed his kidney function, just as it destroyed his sister’s. Jones spent 13 years on dialysis before he got a transplant. He had a terrible infection in the arm where the fistula for dialysis was placed and nearly needed it amputated. Today, there is a long, wide scar from his wrist to shoulder.
Jones battled depression at some points in his life. By the time he was on dialysis in his 40s, though, he began thinking differently. “I didn’t let it get me down,” he says. “What’s the point? I’d still have the sickle cell disease anyway. A bad attitude wouldn’t change anything.”
His family, once upon a time, didn’t believe he could care for himself once he lost his sight. Thirty years later, he continues to live alone with daily help from a home health aide. He is active in his church, attending services via online conferencing. He belongs to a book club. He travels to visit his daughter, who lives in South Carolina. He buys art. Above his couch are three brightly painted scenes from Mexico and the American South. “I know what I am looking for,” he says. “I describe it and people find it for me.”
Researchers are working on other interventions that should lessen the severity of the disease and do a better job of preventing widespread damage. There are more than 40 different medications being developed to treat different aspects of sickle cell disease, including novel ways to reduce or eliminate pain crises.
Right now, there are additional measures to lessen pain crises, notably L-glutamine, which was approved for sickle cell treatment in 2018. When taken with hydroxyurea, the drugs work together to reduce pain crisis occurrences. Then, there are proven strategies including keeping patients well hydrated, oxygenated, and vaccinated. Regular blood transfusions or hemoglobin exchanges are also very effective, Friedman explains, but not without their own risks.

Embracing change

“It’s a very exciting time in sickle cell disease,” says Dr. Biree Andemariam, director of the New England Sickle Cell Institute in Connecticut and chief medical officer for the Sickle Cell Disease Association of America (SCDAA), the largest organization representing people with the disease. The organization’s 47th annual convention in October bustled with patients and caregivers, researchers, doctors, healthcare professionals, and pharmaceutical companies from around the world talking about the future of therapy. The theme was embracing change.
“Not only have the results of bone marrow transplants and gene therapy been very encouraging, but there are numerous companies and organizations aggressively seeking treatment for those who may not be good candidates for those therapies,” Andemariam says. “The patient and caregiver community is ready,” Andemariam adds. “These advances have been long anticipated and our community is ready to be engaged in the development of the therapeutic pipeline.”
Aside from therapy, adult patients still desperately need knowledgeable physicians to understand what it takes to treat the illness and do so aggressively. “It was harder in the past,” Friedman says. “People are more knowledgeable now. But misinformation is still rampant.”
Friedman hopes for the day when children and young adults are cured by gene therapy. “My practice will be older people,” she says. “It would be amazing. There are other drugs coming down the pike, so the people who are older won’t be left out in the cold.”
Today, due to the disease and the potent painkillers he needs, Jones is facing kidney failure for the second time in his life and the possibility of years on dialysis while waiting for a transplant. He may not live long enough to receive a transplant. He has some decisions to make. At the same time, he’s focused on passing on his own story—he’s working on a book about his life with the disease. He says he’s excited about the advances in therapy, even cure, for sickle cell disease—even though they arrived too late to help him.
“I pray for the next generation,” Jones says. “I want people to read my story and learn how to live with sickle cell disease, until they don’t have to.”
Next Steps and Useful Resources
Meet Dr. Ilene Friedman and Dr. Banu Aygun.
The Sickle Cell Disease Association of America is dedicated to advocating for people affected by sickle cell conditions and advancing the search for a universal cure.
Cohen Children’s Hospital treats more than 500 children and adolescents with sickle cell disease and is one of the largest programs in the tri-state area.
Thinking of donating blood? Here are 5 things you should know.