First Gene Therapies Approved for Sickle Cell Disease: What Do They Spell for Patients?
In December 2023, the U.S. Food and Drug Administration announced its approval of two gene therapies for sickle cell disease—the first of their kind for the condition.
Casgevy™ (exagamglogene autotemcel), a cell-based gene therapy developed by CRISPR Therapeutics using its CRISPR/Cas9 genome editing technology, was approved for use in patients 12 years and older with recurrent vaso-occlusive crises (VOCs). Lyfgenia™ (lovotibeglogene autotemcel), also a cell-based gene therapy by bluebird bio, was similarly approved for treating patients 12 and up with a history of VOCs; it uses a lentiviral vector for genetic modifications.
“This is absolutely a development that physicians treating sickle cell disease are excited about,” says Jeffrey Glassberg, MD, Professor of Emergency Medicine, and Medicine (Hematology and Medical Oncology), at the Icahn School of Medicine at Mount Sinai, and Director of the Mount Sinai Center for Sickle Cell Disease.
For a long time, sickle cell disease could only be cured with a bone marrow transplant, but that procedure involves challenges, starting with finding a match and also including the potential for complications, Dr. Glassberg says. “With these gene therapies, we’re taking stem cells from your own blood and taking it to a manufacturing facility to edit the DNA. When we give the stem cells back, you begin making new blood that’s yours without sickle cell disease,” he says. “This resolves a lot of the limitations of a bone marrow transplant.”
How do Casgevy and Lyfgenia work in curing sickle cell disease, and how do they differ from bone marrow transplants? Dr. Glassberg explains in this Q&A.
What goes on in a bone marrow transplant?
So with bone marrow transplant, you need a match. You need somebody to donate the bone marrow. While it’s unlike an organ transplant—where you’re waiting for an organ to become available either through a donation or after someone dies—there is a registry where people are willing to donate. However, finding a 100 percent match is tricky. If you’re lucky, you might have a sibling where their marrow matches perfectly. If not, it’s a rigorous search through this registry.
We can do bone marrow transplants with only half-matches, but those don’t work as well. And even for well-matched transplants, there remains the risk of developing a complication called graft-versus-host disease (GvHD). That is a condition where the donor immune cells recognize the host as foreign and attack the recipient’s body cells. GvHD can be pretty common—occurring in about 50 percent of cases—but only a small percentage turn into catastrophic GvHD.
Jeffrey Glassberg, MD, Director of the Mount Sinai Center for Sickle Cell Disease
What is sickle cell disease?
Sickle cell disease is a group of inherited blood disorders, where a mutation in hemoglobin—a protein in red blood cells that delivers oxygen to tissues—causes the red blood cells to develop a sickle shape. These sickled cells can restrict blood flow in blood vessels and deliver oxygen inefficiently, which can cause pain or organ damage—also known as vaso-occlusive crises. This condition affects approximately 100,000 people in the United States and is most common in Black people. Even with good management, the life expectancy of a person with sickle cell disease is around 50 years
How do the gene therapies avoid these issues?
With the gene therapies, the patient is essentially still going through a bone marrow transplant. The individual still receives a large amount of toxic chemotherapy to kill off existing stem cells, and receives new cells. However, the difference is that it is your own stem cells taken out and fixed. You are donating marrow to yourself, so it will always be a 100 percent match when reintroduced to your body and would not attack the host.
What are the technology differences behind the two gene therapies?
Casgevy uses CRISPR/Cas9, which is basically a protein discovered from bacteria that can cut tiny pieces out of your DNA. The therapy uses CRISPR to turn down a gene called BCL11A, which suppresses the production of fetal hemoglobin after babies are born and activates beta hemoglobin, which is affected by the sickle-cell mutation. By turning down that gene, the patient stops making adult hemoglobin and switches to making fetal hemoglobin.
Lyfgenia uses a lentivirus to create a so-called transgene. The lentivirus drops in a whole gene which contains instructions for producing functional hemoglobin. This approach produces a type of hemoglobin called HbAT87Q, which works even better than regular adult hemoglobin and can be identified with a lab test. The differentiation is helpful in telling exactly how well the gene therapy is working by the amount of HbAT87Q.
In a way, for both fetal hemoglobin and HbAT87Q, they work slightly better than regular hemoglobin for adults with sickle cell disease. Both have similar or slightly better oxygen-binding affinity, and each possesses “anti-sickling” globins that limit or inhibit hemoglobin S levels, which are tied to the sickling of red blood cells.
Are these gene therapies available at Mount Sinai?
Yes, we’ll be doing the therapies starting in late February. We’ve got four patients approved already, and have a list of dozens of people who are being evaluated. You can make an appointment at the Mount Sinai Sickle Cell Disease Center.
To call Mount Sinai Sickle Cell Disease Center
212-241-3650
What goes into the process of receiving these therapies?
It’s a long road. It starts with a visit at a sickle cell disease center. If the physicians have not identified any big reasons why you should not be a candidate, you’ll be referred to a gene therapy team—these doctors also work with bone marrow transplants. They will ensure any medical issues before and after the therapy are accounted for.
Administrative and finance teams will work with you to ensure these therapies are covered. These are expensive products—about $2 million or so—and each gene therapy is an individual negotiation and contract between the insurance company and drug company.
If everything is approved, you’ll make an appointment to come into the hospital for a procedure called apheresis. It’s almost like dialysis, where you’re hooked up to a machine. Your blood is pulled into the machine where stem cells are extracted over a period of about six hours. The stem cells are sent off to a manufacturing facility where the drug company does the gene therapy. This could take up to six months.
When the product is ready, you’ll check into the hospital again. You’ll be given chemotherapy to kill off all the stem cells in your body that make blood. Once all the stem cells are gone, a bag containing the gene therapy gets transfused into you, and the modified cells find their way back into the bones and start making blood that doesn’t have sickle cell disease.
Similar to a bone marrow transplant, you’ll be in the hospital for four to six weeks, because you have no immune system following the transfusion, and the product takes about a month to get into your body. This would be the biggest danger period of the whole process. But after that, you leave the hospital pretty much cured of sickle cell disease, though you might have to come back for several checkups.
What are some risks associated with the gene therapies?
Like in bone marrow transplant, the involvement of chemotherapy does carry a small risk of death. And there is a small risk of secondary cancers from the chemotherapy. It is very likely a person opting for this therapy might not be able to have children afterward unless you preserve your eggs or sperm. After the therapy, you would have to be careful for a while because your immune system is still reconstituting itself, and a simple case of influenza can make you much sicker than it normally would.
Who might be ideal for this sort of therapy?
The sickest of patients would be too frail to undergo chemotherapy, and a patient with mild disease wouldn’t find the risk-benefit attractive. It would essentially be someone with severe disease who isn’t responding well to current available drugs, but is strong enough to undertake the risk of chemotherapy to not have sickle cell disease anymore.
In adult medicine, we have moved away from paternalism, so our approach is: if you have sickle cell disease, and you understand the procedure, risks, and alternatives, and you still want to opt for the gene therapy, we will support you and do our best to help you succeed. It’s a shared decision-making process with the patient to make sure they understand what they’re getting themselves into.
In children for whom this therapy is appropriate, it’s a different approach. It’s more a medicine-based approach, where you only reach for the extreme care when you’ve exhausted all other options and you can say with relative certainty that the child would otherwise be certain to experience bad outcomes. An example would be if a child had had a stroke after maximal treatment and continued to have another stroke, then a transplant or gene therapy could be considered.
There might be many who would not opt for this, given that there are many good treatments that could help manage the condition, as well as more drugs in development. But these gene therapies open up options for a tremendous number of people. They are a cure for sickle cell disease as much as a bone marrow transplant is considered a cure. We know from bone marrow transplant patients who have lived decades after the procedure that the benefit continues to be a durable effect for the rest of their life. While we can’t predict how patients will fare decades down the road, since the first patients for these gene therapies got them in 2014, we are hopeful they will see similar durable benefit as well.
