Two gene therapies have been approved by the Food and Drug Administration for treating sickle cell disease, one of which is the first therapy based on CRISPR/Cas9 technology to receive regulatory approval in the United States.
Sickle Cell Disease and Treatment Challenges
Sickle cell disease is a devastating condition in which red blood cells deform into a sickle shape and block blood vessels. It affects about 100,000 people in the United States, often among individuals of African descent. The disease leads to anemia, vaso-occlusive events (painful episodes that deprive tissues of oxygen), strokes, progressive and irreversible organ damage, reduced quality of life, and early mortality.
Limited Treatments for the Disease and New Gene Therapy
Available treatments so far have been limited. A bone marrow transplant from a genetically matched sibling can cure the disease in more than 90 percent of cases, but only about 20 percent of patients have a genetically matched sibling. There are also several medications available and supportive care, but these treatments mainly reduce the severity of the disease. In contrast, new gene therapies have shown high efficacy in preventing vaso-occlusive events.
How CRISPR/Cas9 Gene Therapy Works
The currently approved CRISPR/Cas9 gene therapy, named Casgevy, works by preventing the deformation of red blood cells through triggering the production of another type of hereditary hemoglobin – fetal hemoglobin (HbF). HbF is optimized for transport, carrying oxygen from the maternal blood to the fetal tissues, and the gene encoding it is switched off after the body is born, transitioning to HbA. Typically, HbF constitutes about 1 to 2 percent of hemoglobin in the body around six months after birth.
HbF can effectively treat sickle cell disease – as hemoglobin carries oxygen well in adults and does not form polymers. Moreover, when mixed with HbS, it hinders the formation of the altered protein itself, preventing the formation of structures that deform red blood cells.
Casgevy activates HbF using the CRISPR/Cas9 system, a gene-editing mechanism originally developed from bacteria that cuts DNA using an enzyme called Cas9. Cas9 can be directed to specific DNA segments using a short guide RNA sequence. In the case of Casgevy, the CRISPR/Cas9 system is targeted to cut a gene that contains a protein called BCL11A, which regulates other genes and is also known as a transcription factor. The BCL11A transcription factor is the protein responsible for shutting off the HbF gene after the body’s birth and its transition to the adult form. With the CRISPR/Cas9 cut, BCL11A is disabled, allowing HbF production to resume.
This process involves harvesting the patients’ stem cells from bone marrow and editing them using CRISPR in a specialized lab. Simultaneously, patients undergo chemotherapy to kill their bone marrow cells to make way for the genetically edited cells that are then reintroduced. Among 31 patients treated with Cagevy and followed for at least 24 months, 29 (93.5 percent) were able to remain free from vaso-occlusive crises for at least 12 consecutive months.
Another Gene Therapy Approved by the FDA
The other gene therapy currently approved by the FDA is Lyfgenia, which uses a lentiviral vector to introduce genes into the human genome. In this case, the system delivers the genetic code for a modified type of hemoglobin designed to counteract the deformation, called HbAT87Q. Among 32 patients treated with Lyfgenia, 28 (88 percent) were free from vaso-occlusive incidents for periods ranging from six to 18 months after treatment.
Approved.
Approval for both gene therapies for patients aged 12 and older.
Additionally, it should be noted that this article is written by Beth Mole, a public health reporter for Ars Technica, who specializes in covering infectious diseases, public health, and microbes.
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