Until recently, the only possible cure for sickle cell disease, an inherited genetic blood disorder most common in people with African ancestry, was a bone marrow transplant, which has its own set of challenges.
Now, people with sickle cell disease (SCD)—which affects an estimated 100,000 Americans and can cause chronic pain, organ damage, strokes, and shortened life expectancy—have additional, potentially curative options. In early December, the Food and Drug Administration (FDA) approved two gene therapies for SCD, one of which is the first approved medication that uses the gene-editing tool CRISPR.
Both treatments—Casgevy™, which is made by Vertex Pharmaceuticals and CRISPR Therapeutics, and Lyfgenia™, by Bluebird Bio—are for people 12 and older. Sickle cell disease is a red blood cell disorder that affects hemoglobin, the protein that carries oxygen throughout the body. These two therapies work in different ways, but both are intended to be a one-time fix, although that will require years of follow-up to know for sure.
With Casgevy, an edit (or “cut”) is made in a particular gene to reactivate the production of fetal hemoglobin, which dilutes the faulty red blood cells caused by sickle cell disease (more on that below). Lyfgenia, on the other hand, uses a viral envelope to deliver a healthy hemoglobin-producing gene.
The therapies are hailed as groundbreaking as they represent the first-ever gene therapies to potentially cure a hereditary condition.
“For many years, we only had one treatment for sickle cell disease, and then medicine advanced to the point where we could offer bone marrow transplant, the first potential cure for sickle cell disease,” says Cece Calhoun, MD, MBA, a Yale Medicine hematologist-oncologist. “But trying to find a good match for a transplant is a big barrier. This new technology uses gene therapy to allow patients to be their own match.”
This is significant, she notes, because a sickle cell crisis—the pain the disease causes—is unpredictable and intense, “akin to how it feels to have a long bone fracture.”
But, says Dr. Calhoun, the pain sickle cell disease causes is not the only problem faced by people with the condition.
“Sickle cell disease impacts every organ. Children are having strokes, and young adults—people in their 30s—are experiencing kidney failure—all because of sickle cell disease. If we can intervene and prevent these complications and let these patients live full lives, that is huge,” Dr. Calhoun says.
Lakshmanan Krishnamurti, MD, chief of Yale Medicine Pediatric Hematology & Oncology, agrees.
“Many can’t have bone marrow transplantation because only about 15% of patients have a matched sibling, and we can find an unrelated donor for only another 10% to 12%. That means we are only helping 25% of patients,” says Dr. Krishnamurti, who was an author on the Lyfgenia study published in The New England Journal of Medicine. “This is a big step forward.”
However, the gene therapies are time-intensive—taking about a year to complete the process—and grueling. As with bone marrow transplants, they require high-dose chemotherapy to kill the faulty stem cells before they are replaced with modified stem cells.
The gene therapies will be available only at large, authorized medical centers because they require advanced care. They are also expensive (estimates put it at $2 to $3 million per patient), and it’s yet to be determined if or how insurance companies, including Medicaid, will cover the treatment.
Dr. Krishnamurti says both treatments will be available at Yale and that anyone interested in learning more should speak to their physician.
Below, Drs. Calhoun and Krishnamurti answer common questions about sickle cell disease and these new gene therapies.
What is sickle cell disease, and why is it so painful?
A person with sickle cell disease has inherited a copy of a faulty hemoglobin gene from each parent. This faulty gene causes red blood cells to become hard, sticky, brittle, and crescent-shaped (like a sickle, or farming tool) instead of the usual smooth, round, and flexible shape.
Brittle cells break down faster, which leads to anemia, a condition in which the blood doesn’t have enough healthy red blood cells. This reduces oxygen flow to the body’s organs and causes symptoms such as fatigue and dizziness.
“These sticky and brittle sickle cells scratch up the sides of the blood vessels and cause inflammation,” Dr. Calhoun says. “They can also block the blood vessels. If the blood can’t get where it needs to go to nourish the organs within the body, that leads to chronic damage.”
All of this causes pain that can range from dull to intense, leading to a sickle cell crisis, which can sometimes be eased by medication or a hospital stay. “We talk a lot about pain with sickle cell disease because it’s unpredictable and is what affects patients’ quality of life the most,” Dr. Calhoun says.
All newborns in the U.S. are screened for SCD with a simple blood test; when family members have a history of SCD, babies can be diagnosed in utero. Medications and blood transfusions have been used to manage complications and pain associated with SCD, but such treatments are not enough for many patients with the disease, the doctors say.
What’s the difference between Casgevy and Lyfgenia?
The goal of genetic therapies for SCD is to treat or cure the disease by changing DNA or adding new DNA.
With Casgevy, the patient’s blood stem cells are edited in a way that makes them produce high levels of fetal hemoglobin, which is produced during fetal development and binds to oxygen more strongly than adult hemoglobin.
“After birth, the body starts to deactivate the gene for fetal hemoglobin. The gene is still there; it’s just turned off,” Dr. Krishnamurti explains. “Casgevy targets the parts of the DNA involved in switching the fetal hemoglobin off and deletes it from the genome. The body then starts to produce fetal hemoglobin, which dilutes sickle hemoglobin.”
Essentially, Casgevy works by reducing the number of sickle cells in the body to a negligible amount, which may permanently ease symptoms.
Lyfgenia, meanwhile, works by taking a piece of a virus (a lentivirus, which belongs to the HIV family) and using it to deliver a functional version of a hemoglobin-producing gene.
“The lentivirus enters the blood-making stem cells, drops off the gene, and then the gene becomes part of the genome, and the virus goes away,” Dr. Krishnamurti says. “While Casgevy activates the native fetal hemoglobin, Lyfgenia uses an artificial gene. But both are trying to dilute the sickle hemoglobin that the body would otherwise continue to make.”
What is it like to be treated with Casgevy or Lyfgenia for sickle cell disease?
For patients, the process to receive either of these two gene therapies is similar, in that they both require multiple hospital visits and chemotherapy, and they are delivered over a period that ranges from eight to 12 months from start to finish.
As a first step, patients receive blood transfusions, which help minimize the number of sickle cells in circulation. Usually, this can be done on an outpatient basis and takes multiple transfusions over a period of two months or so. Next, they stay in the hospital for a week to have their stem cells collected. Then, the stem cells are sent to a processing facility where either CRISPR technology or the viral vector (another tool used to deliver genetic material to cells) is employed to modify the patient’s stem cells. This takes four to six months.
Once the cells are ready, the next step is two weeks of chemotherapy to kill the cells that make faulty hemoglobin and to make sure the body doesn’t reject the cells. The modified blood stem cells are then transplanted into the patient via an intravenous infusion. The patient remains in the hospital for a month while the cells begin to take hold, and the immune system starts to show signs that it is coming back in a robust way, Dr. Calhoun says.
Once the bone marrow is functioning, the patient can go home with three oral medications that will need to be taken for three months.
While bone marrow transplant remains an option, Dr. Krishnamurti says the gene therapies are less burdensome. “Typically, after a bone marrow transplant, patients stay in the hospital for six weeks, they're on immunosuppression medication for six to 12 months, and they're taking a dozen medicines,” he says. “With these gene therapies, the immune system recovers much faster because they use the patients’ own cells.”
How safe and effective are these new gene therapies for sickle cell disease?
Casgevy was studied in a multicenter trial involving adult and adolescent patients with a history of sickle cell crises during each of the past two years. A total of 44 patients were treated with Casgevy, and 31 remained in the study long enough for data to be collected. Of those 31, 29 (93.5%) reached the goal of having no pain episodes for at least one year during the two-year follow-up period. Trials are ongoing.
The most commonly reported side effects included mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, headache, and itching, but there were no notable safety concerns. These side effects are from the chemotherapy, not the gene therapies, says Dr. Calhoun.
Lyfgenia was studied in a two-year multicenter trial of adults and adolescents with a history of sickle cell crises. Twenty-eight (88%) of the 32 patients had no pain episodes for six to 18 months after their infusion.
Common side effects included sores on the lips, mouth, and throat, as well as fever and low white blood cell count, all of which are consistent with having received chemotherapy and due to the underlying disease, the FDA noted.
However, blood cancer occurred in two patients treated with Lyfgenia, and a black box warning is included on its label.
It should also be noted that the type of chemotherapy used for these gene therapies and for bone marrow transplants can lead to infertility. Fertility preservation is an option for some patients and should be discussed with their physician.
Who is a candidate for these gene therapies for sickle cell disease?
Patients interested in knowing more about gene therapy should have a conversation with their primary hematologist, Dr. Calhoun says.
If they are referred to a specialized center, such as Yale’s Sickle Cell Program, they would meet with more specialists, including the transplant team.
“We would need to think about objective factors, such as how their organs function, if they can handle the chemotherapy that’s required, and if they have had severe disease that would make the risk outweigh the benefits of this procedure,” Dr. Calhoun says. “Then, there are more subjective factors. It takes a year; it's not an easy process. Do you have a support system? Who will help you navigate these challenging ups and downs?”
Even if the timing is not right for a particular patient, it’s still a good idea to explore various treatment options, Dr. Krishnamurti says.
“There is more in the pipeline. Today, someone might not be a candidate because they have organ dysfunction, but in the next few years, we will be further along with the science, and there may be a new treatment for that person,” he says. “Already, the vast majority of sickle cell patients have a treatment option available to them, and more will be coming. We should celebrate the advances we are making.”