The U.S. Food and Drug Administration (FDA) has approved the first CRISPR gene-editing therapy for sickle cell anemia. The treatment named “Exa-cel,” produced by Vertex and CRISPR Therapeutics, has demonstrated its ability to cure the disease for at least one year. With this decision, the United States becomes the second country to approve a CRISPR treatment, following the approval of “Exa-cel” for sickle cell anemia in the UK in November.
What is sickle cell anemia and how does the new CRISPR treatment work?
The CRISPR system used in “Exa-cel” targets genes that produce hemoglobin, the protein that carries oxygen in the blood cells. In the case of sickle cell anemia, also known as sickle cell disease, mutations in a gene called HBB affect the protein’s structure, causing it to twist and take on a curved shape instead of a round one as it normally should. These curved cells block blood vessels, leading to severe pain and extreme fatigue. In beta thalassemia, which is occasionally associated with sickle cell disease, the body does not produce enough hemoglobin or red blood cells, resulting in symptoms caused by low oxygen levels in the blood. Symptoms include fatigue and growth problems in children.
“Exa-cel” directs an enzyme called Cas9 to a gene called BCL11A, which normally prevents the body from producing a type of hemoglobin that is found only in fetuses. Cas9 disables BCL11A in the bone marrow stem cells, where red blood cells are produced, by cutting the gene’s DNA, and the cells begin to produce fetal hemoglobin and create red blood cells with the normal round shape. In the new treatment, a person’s stem cells are removed, edited using “Exa-cel,” and the remaining unedited bone marrow is destroyed, before reintroducing the edited cells.
As these edited cells reestablish themselves in the body over time, “Exa-cel” is considered a “curative” treatment that theoretically lasts for the recipient’s lifetime, although Vertex and CRISPR Therapeutics have not followed up most trial participants for less than two years.
How effective is the treatment?
So far, “Exa-cel” has only been tested on about 100 people with sickle cell disease or beta thalassemia. However, in 2019, the FDA granted the companies “fast track” approval that allows them to test the treatment on smaller groups of people than is typically required.
In these ongoing trials, 29 out of 30 participants in the study with sickle cell disease did not experience any pain for one year in the 18 months following blood transfusions using “Exa-cel.” Additionally, 39 out of 42 beta thalassemia patients did not require blood or bone marrow transplant – the standard treatment for this condition – for one year after “Exa-cel” intervention. Vertex and CRISPR Therapeutics continue to monitor the remaining participants who have not yet reached this timeframe and will follow all participants for up to 15 years.
What are the risks?
Data presented to the FDA indicates that “Exa-cel” does not have significant negative health effects, although it may cause side effects such as nausea and fever. However, Debon notes that participants have not been followed for a long time, and problems may arise later.
Among other concerns raised by the FDA is that the Cas9 enzyme may remain active and cut the genome in places other than BCL11A, leading to off-target mutations. The companies have modeled the most likely places in the genome where the enzyme could cut and found no evidence of such occurrences in trial participants. “As with any new treatment, we remain cautiously optimistic,” says Debon.
In addition
To “Exa-cel”, what are some other promising treatments for sickle cell disease?
The “Lovo-cel” treatment approved by the U.S. Food and Drug Administration today, produced by bluebird bio, uses a viral vector to deliver a functional copy of the adult hemoglobin gene and insert it permanently into the person’s genome. Data submitted by bluebird bio to the FDA showed that “Lovo-cel” was effective in 36 individuals followed for 32 months. There are several studies looking into other types of gene therapies for sickle cell disease and beta-thalassemia that provide normal copies of HBB or other genes to the body.
Researchers have found that genetically matched bone marrow transplantation can also treat sickle cell disease. In this treatment, which is already widely used for certain types of cancer, the patient’s bone marrow cells are replaced with cells from genetically similar parents or siblings who share 50% genetic similarity with the recipient but do not have the disease. Results to be presented next week at the American Society of Hematology’s annual meeting show that 88% of adults who received these transplants continued to produce normal red blood cells after two years. Debon says this technique could be particularly beneficial in low- and middle-income countries because it is likely to cost much less than gene editing or gene therapy.
Will “Exa-cel” or “Lovo-cel” be available to all individuals with sickle cell disease?
Like most gene editing treatments, “Exa-cel” and “Lovo-cel” are likely to be very expensive. The companies Vertex, CRISPR Therapeutics, and bluebird bio have not disclosed how much their treatments will cost, but estimates suggest that the price for each could reach up to $2 million per patient. It remains unclear whether insurers, particularly government services like Medicaid, will cover the costs of treatments or under what circumstances they will do so. Sickle cell disease disproportionately affects individuals of African descent, including African Americans, who are more likely to have public insurance through Medicaid than any other groups in the United States.
Debon states that the decision on whether to pursue gene editing with CRISPR technology or to opt for another approach such as genetically matched bone marrow transplantation should be a shared decision among patients, their families, and their doctors. Even if gene editing proves to be more effective in permanently treating the disease, it is likely to be less widely available and may take longer than a bone marrow transplant from a donor.
However, Debon says that “Exa-cel” is a good step in the right direction and expects the technology to improve with further knowledge about CRISPR therapies in the coming decade. “This is the first mile in a marathon,” he says.
Source: Sarah Reardon, a freelance journalist based in Bozeman, Montana. She is a former reporter for Nature, New Scientist, and Science and holds a master’s degree in molecular biology.
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