The U.S. Food and Drug Administration has made a significant advancement in the treatment of sickle cell disease (SCD) by approving two new cell-based gene therapies, Casgevy and Lyfgenia, for patients aged 12 and older. Sickle cell disease is a genetic blood disorder that affects about 100,000 people in the U.S., predominantly African Americans, and is characterized by a mutation in the hemoglobin protein. This mutation leads to red blood cells adopting a crescent shape, which can obstruct blood flow and oxygen delivery, causing severe pain, organ damage, and potentially life-threatening complications.

The mutation in the hemoglobin protein that characterizes sickle cell disease (SCD) alters the structure and function of hemoglobin, which is crucial for transporting oxygen in the blood.  Hemoglobin is made up of four protein subunits, and in SCD, a mutation occurs in the gene that codes for the beta-globin subunit. This mutation leads to the production of an abnormal form of beta-globin known as hemoglobin S (HbS). In normal RBC (red blood cells), hemoglobin (a protein) has a particular shape. We learned in AP biology that proteins need a specific shape to carry out their function. In people with sickle cell anemia, that protein is mutated doesn’t have the correct shape, and cannot carry out its function.  The reason it doesn’t have the right shape is that the mutated hemoglobin sequence is modified at a single amino acid.

Under certain conditions, such as low oxygen levels, dehydration, or acidosis, HbS molecules tend to stick together, forming long, rigid chains within the red blood cells. These chains distort the shape of the red blood cells from their normal, flexible disc shape to a rigid, crescent or “sickle” shape. Unlike normal red blood cells that can easily move through the bloodstream, these sickled cells are stiff and sticky. Its interesting how such a small change can have such a significant effect in our body!

The crescent-shaped cells can get trapped in small blood vessels, blocking the flow of blood. This blockage prevents the delivery of oxygen to nearby tissues, which can cause pain and damage to tissues and organs. Furthermore, the sickled cells are more prone to breaking apart, leading to hemolysis (the destruction of red blood cells), which can cause anemia (a shortage of red blood cells) and other complications. The recurring blockage of blood vessels and the chronic shortage of red blood cells and oxygen supply lead to the severe symptoms and complications associated with sickle cell disease, including acute pain crises, increased risk of infections, and organ damage.

Casgevy stands out as the first therapy of its kind to employ CRISPR/Cas9, a groundbreaking genome editing technology, to modify patients’ hematopoietic stem cells. This process aims to increase the production of fetal hemoglobin in patients, which helps prevent the sickling of red blood cells. On the other hand, Lyfgenia uses a lentiviral vector to genetically modify blood stem cells to produce a variant of hemoglobin that reduces the risk of cells sickling. Both therapies involve modifying the patient’s own blood stem cells and reintroducing them through a one-time infusion, following a high-dose chemotherapy process to prepare the bone marrow for the new cells.

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These therapies represent a major leap forward in treating sickle cell disease, addressing a significant unmet medical need for more effective and targeted treatments. The FDA’s approval of Casgevy and Lyfgenia is based on the promising results of clinical trials, which demonstrated a substantial reduction in the occurrence of vaso-occlusive crises, a common and painful complication of SCD, among treated patients.

The approval of these therapies also underscores the potential of gene therapy to transform the treatment landscape for rare and severe diseases. By directly addressing the genetic underpinnings of diseases like SCD, gene therapies offer a more precise and potentially long-lasting treatment option compared to conventional approaches. The FDA’s support for such innovative treatments reflects its commitment to advancing the public health by facilitating the development of new and effective therapies.

However, it’s important to note that these therapies come with risks and side effects, such as low blood cell counts, mouth sores, and the potential for hematologic malignancies, particularly with Lyfgenia, which carries a black box warning for this risk. Patients receiving these treatments will be monitored in long-term studies to assess their safety and effectiveness further. Despite these challenges, the approval of Casgevy and Lyfgenia marks a hopeful milestone for individuals with sickle cell disease, offering new avenues for treatment and the promise of improved quality of life. If you were diagnosed with Sickle cell disease, would you try this no-treatment when available? Do the positives outweigh the negatives? Let us know!

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