Sickle Cell Disease: Exploring Gene Therapy with Casgevy and Lyfgenia

How is gene editing technology allowing for new, curative treatments for sickle cell disease?

For kids with sickle cell disease, treatment options have historically been limited by the need for a well-matched, related bone marrow donor. Only a small minority of patients are fortunate enough to have a match in a relative, and unrelated donor transplant is limited by the fact that the disease disproportionately impacts the Black community, which remains underrepresented on donor lists. What’s more, this type of transplant carries a high risk of graft rejection and graft versus host disease. In late 2023, though, the U.S. Food and Drug Administration (FDA) approved two new therapies for patients 12 and up, called Lyfgenia and Casgevy, that allow for autologous bone marrow transplant, which uses the patient’s own, altered cells instead of a donor.

Sickle cell disease is a set of genetic blood disorders in which hemoglobin, a protein within red blood cells, is abnormal. This causes significant changes in the shape and form of red blood cells that lead to severe anemia, pain crises and more. With such limited treatment options, people with the disease are often left to manage a lifetime of symptoms, pain, organ damage and early mortality, or risk the complications of unrelated, or allogeneic, donor transplantation.

Experts at Children’s Hospital Colorado currently care for more than 220 children with this difficult disease, and thanks to the FDA’s recent decision, these patients now have access to new, life-changing therapies. In March 2024, Children’s Colorado became one of the first qualified treatment centers (and the only one in the region) for the newly FDA-approved Lyfgenia therapy. Its providers will soon begin the treatment for children locally, as well as kids and adults from Montana, Wyoming, New Mexico, Kansas, Texas, Nebraska and South Dakota.

The two FDA-approved treatments each take a different approach to helping patients’ bodies produce healthy hemoglobin that forms non-sickling red blood cells. Kids with sickle cell disease typically don’t have major complications as babies. That’s because they make a different type of hemoglobin called fetal hemoglobin, which blocks sickling. As kids with this condition grow older, the BCL11A gene is activated, causing the body to switch from producing fetal hemoglobin to the mutated sickle hemoglobin. Casgevy uses CRISPR gene editing to decrease expression of the BCL11A gene, allowing the body to produce fetal hemoglobin once again. Lyfgenia, meanwhile, infuses a new copy of a mutated HBB gene, which makes beta globin, ensuring the body produces normal non-sickling hemoglobin after treatment.

Leaning on experience with sickle cell disease

Because of its large population of patients with sickle cell disease and its longstanding commitment to providing treatments to these patients, Children’s Colorado will assume the important task of providing access to these therapies.

“We are considered a high-volume transplant center for patients with sickle cell disease,” says Christopher McKinney, MD, Children’s Colorado hematologist. “We’ve participated in multiple allogeneic and autologous curative therapy trials for sickle cell disease and are usually one of the highest accruing centers. So, we have a lot of experience in transplant for sickle cell disease, as well as the supportive care that goes along with that.”

In particular, the team’s experience with a vital part of the treatment plan, apheresis, sets Children’s Colorado apart. Apheresis involves mobilizing and collecting a patient’s stem cells and is particularly tricky in patients with sickle cell disease.

“After administering a medication to help patients release stem cells from the bone marrow into the blood, we hook them up to a machine to isolate and collect those stem cells. This process is different in patients with sickle cell disease and technically a lot harder to do,” Dr. McKinney explains. “Few centers across the country have experience doing this. Because we have participated in gene therapy clinical trials and have done it for previous patients, we have a substantial amount of experience with mobilizing and obtaining those stem cells, which is important for safely and efficiently obtaining enough cells for gene therapy.”

It can take months and multiple rounds of apheresis to collect enough stem cells for the treatment, and at this point, the journey is far from over. Patients must then undergo roughly three months of red-cell-exchange transfusion while the cells are being manufactured, during which patients get donor blood to keep the number of sickle cells in their blood low and prevent complications. Then, they have four days of high-intensity chemotherapy designed to remove their existing bone marrow and make space for the genetically altered stem cells. After stem cell infusion, the patients then spend the next four to six weeks getting supportive care in the hospital while waiting for the stem cells to grow. This extensive process requires specialized sickle-cell-specific expertise, experience and equipment to ensure good outcomes — something available at only a limited number of centers nationally.

A next-generation gene therapy treatment

In addition to providing treatment and care for kids and adults in the surrounding states, Dr. McKinney and his research team at Children’s Colorado are currently enrolling patients in a new sickle cell disease gene therapy clinical trial through the Ruby EDIT-301 study. Using next-generation CRISPR technology, which allows for greater precision in gene editing, the gamma globin gene promotor is altered to a naturally occurring sequence in patients born with high levels of fetal hemoglobin so that it becomes resistant to the effects of BCL11a, the protein that stops the body’s production of fetal hemoglobin. This increases healthy blood cells and decreases sickle cells.

Preliminary data presented at the American Society of Hematology meeting in December 2023 showed rapid increases in production of fetal hemoglobin and resolution of severe pain crises in all patients. Over the next two years, the team will monitor them to understand whether long-term results match the promise of preliminary data.

A year after his own transplant, 28-year-old Xavius Hymes, shared his experience as an early recipient of gene therapy at Children’s Colorado with Colorado Public Radio (CPR). “It was a total change in my energy level and how I was able to just go about life! I didn’t have to worry about having pain crises every other day or every month,” Hymes told CPR.

This is exactly the outcome Dr. McKinney hopes for every child and adult living with sickle cell disease. “This is a really exciting time, because for so long they had so few treatment options,” he says. “I see patients when they're diagnosed on newborn screens, and their parents are incredibly nervous and scared about what's going to happen to their child. Now we get to tell them that it is very possible they might not need to live with sickle cell disease forever.”