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Victoria Gray never remembers a moment when she didn’t have sickle cell disease. She was diagnosed with the condition at 3 months of age after she cried so hard during a bath that she was taken to the emergency room. For Gray, who has no close relatives with the disorder, that was the beginning of unrelenting pain, ER visits, hospitalizations and treatments that robbed her of much of her childhood and adult life.
Gray became unable to take care of herself and her family. In hopes that she could improve her life by even 50%, Gray bravely chose to be the first patient to enter a clinical trial using a CRISPR editing drug to treat sickle cell disease. Four and a half years later she, and dozens of others from the trial, are doing amazingly well.
The first marketed medicine based on gene-editing CRISPR (clustered regularly interspaced short palindromic repeats) technology, called Exa-cel, is expected to receive approval from the Food and Drug Administration this week for use in selected patients with sickle cell disease. Exa-cell recently received approval in the U.K. for treatment of both sickle cell and beta-thalassemia.
“I never imagined I could feel this well and do so much,” Gray said on a recent Zoom call, after we first met at a Concert Genetics meeting in Nashville in October.
Sickle cell disease is a lifelong, inherited condition that affects hemoglobin, a protein that carries oxygen throughout the body in red blood cells. Normal red blood cells are disc-shaped and flexible enough to move easily throughout the blood vessels. But in people who inherit two mutations for sickle cell disease, abnormal hemoglobin forms and causes the red blood cells to become sickle-shaped, jamming blood flow and often leading to pain and serious health problems.
Sickle cell can occur in people of any ancestry, but it’s most common in those who identify as Black. In the United States about 1 in 13 African-American babies are born with one copy of the sickle cell mutation, and 1 in 365 are born with two copies, meaning they have the disease. In comparison, 1 in 16,300 Hispanic-Americans are born with this condition. More than 20 million people worldwide have sickle cell disease.
Gray faced excruciating pain crises and subsequent visits to the emergency room, followed by hospitalizations every two to three months as a child. “It felt like glass was flowing through my veins,” she described. She missed countless days of school, holidays with her family and the chance to play sports and participate in activities. “I felt isolated, different and alone. No one else I knew had sickle cell,” Gray explained. She later attended college to become a nurse but was not able to complete her degree due to sickle cell-related delays in her education. “I felt like I couldn’t accomplish anything.”
During one of her many crises, Gray saw Dr. Haydar Frangoul at Sarah Cannon Pediatric Hematology/Oncology & Cellular Therapy at TriStar Centennial Medical Center in Nashville, Tennessee. Frangoul raised the option of a new clinical trial using CRISPR technology. Gray had been focused on having a bone marrow transplant but liked the fact that CRISPR would not put her at risk for serious rejection complications that can occur with bone marrow from a donor. Learning that she could still pursue a transplant if CRISPR failed, Gray agreed to be the first person with sickle cell to be treated with CRISPR therapy.
She underwent comprehensive testing to ensure her organs were healthy and then stem cell collection that was sent to a manufacturing facility for gene editing. Exa-cel was used to molecularly edit Gray’s cells to turn on production of a form of fetal hemoglobin that most babies stop making a few months after birth. The theory was that the CRISPR therapy would trigger the creation of fetal hemoglobin in Gray that would compensate for the normal adult hemoglobin she could not make due to her sickle cell mutations.
At Sarah Cannon Research Institute and HCA Healthcare’s The Children’s Hospital at TriStar Centennial, Gray started a grueling chemotherapy regime to eliminate all stem cells from her bone marrow, including those that produce the sickled cells. On July 2, 2019, she received her newly edited CRISPR cells, pushed into her body through a catheter in her chest within 10 minutes. Gray cried when the procedure was over. “I believed my life was going to change,” she recalled. “I was reborn that day.”
Gray was in isolation in the hospital for 30 days with her father there to keep her company. She was then moved to an apartment within walking distance of the hospital, where she remained in isolation for two weeks with her mother-in-law followed by four weeks with her husband. Gray moved home to Mississippi with her family, but she experienced no changes to her sickle cell symptoms and remained on medication to control her pain.
About seven months after she received her transfusion, Gray woke up one morning and thought something was wrong. In fact, she feared she was dying. She was experiencing the absence of pain. Her sickle cell pain wasn’t better—it was gone. Her symptoms did not taper off—they abruptly disappeared. Gray has had not one pain crisis, hospitalization or blood transfusion since that day. She can fully participate in her life and the lives of her husband and four children. She can shower, dress herself, do the laundry, make meals and be in the stands at her children’s events. Gray can work outside the home and even fly on airplanes—something she never dreamt she would be able to do. “Coming from someone who once was hopeless, I now feel there are no limits to what I can do.”
CRISPR technology has the potential to treat dozens, if not hundreds, of conditions including beta-thalassemia, hemophilia, diseases of the eye, some forms of cancer and infectious diseases; however, this therapy has limitations. The Exa-cel process is prohibitively expensive, likely costing millions of dollars. Insurance may cover some or all of the associated expenses, but that is currently unknown. The process requires chemotherapy, which can cause infertility and low blood counts and can increase the risk of serious infections. Moreover, CRISPR Exa-cel therapy cannot reverse damage already caused by sickle cell disease, there are less than five years of long-term data on its effects and it is not scalable to the 20 million people worldwide with sickle cell due to the expensive and complex pathway to treatment.
But this therapy gave life back to Victoria Gray, who is now a speaker and patient advocate, and dozens of other sickle cell patients who have undergone this treatment.
Dr. Frangoul, a hematologist who has cared for sickle cell patients for decades and watched the physical, emotional and real-world consequences that this disease causes, told me he’s excited to finally say to his patients, “Hope is on the way.”
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