An overview of gene therapy for sickle cell disease

Red blood cells are smooth, doughnut-shaped cells that carry oxygen from the lungs to different tissues throughout the body. These cells also collect and carry carbon dioxide to the lungs so it can be exhaled. Essential to this process is a protein called hemoglobin, an iron-rich protein capable of binding to both oxygen and carbon dioxide depending on the circumstances.

Sickle cell disease is a genetic blood disorder that affects the production of hemoglobin. More specifically, sickle cell disease affects the production of beta-globin, one of the main components of hemoglobin.

When a person has sickle cell disease, the body produces abnormally shaped beta-globin. This results in abnormally shaped hemoglobin, which results in abnormally shaped red blood cells. Instead of the smooth, doughnut-like shape, red blood cells are shaped like crescents or sickles.

This causes a number of problems. Sickle cells do not function like normal cells. They break apart easily in the bloodstream, leading to low levels of red blood cells (anemia).

Sickle cells can also get stuck in small blood vessels and block blood flow (and oxygen supply) to organs, causing severe pain, organ damage, and other serious complications. These episodes are known as vaso-occlusive crises (VOCs) or pain crises.

Treatment for sickle cell disease can include:

• Medications that may help reduce the frequency of pain crises
• Pain-relieving medications given during a pain crisis
• Blood transfusions to prevent complications, including stroke
• In young children, medications to lower the risk of infections
• A blood stem cell transplant (also called bone marrow transplant), which is a potential cure but requires a matched donor and has a risk of serious side effects

Mutations to the HBB gene and gene therapy

People with sickle cell disease have a genetic mutation in the HBB gene, a segment of DNA that contains instructions for making beta-globin. These mutations drive the production of abnormal beta-globin.

Gene therapies are new and emerging treatments for sickle cell disease that aim to modify and correct the mutated HBB gene. This will increase the amount of healthy hemoglobin and decrease the amount of abnormal hemoglobin.

Gene therapies have the potential to cure sickle cell disease. They also require intensive chemotherapy and a long recovery process. Not everyone will be a candidate for this treatment.

How does gene therapy work?

Gene therapy begins with the collection of blood stem cells, which are immature cells that can develop into different types of blood cells. The collected blood stem cells are sent to a lab where one of several processes will be used to alter the mutated HBB gene:

• In gene addition, a normal HBB gene is added to the collected stem cells. If successful, this will allow the stem cells to produce normal hemoglobin.
• With gene editing, an alteration is made to the HBB gene inside the collected stem cells by making a cut in the DNA. This cut can silence or replace the mutated gene, depending on the method being used.

What steps are involved in receiving gene therapy?

Gene therapy is an intensive process that can take up to a year to complete:

1. Evaluation. Your healthcare team will perform exams and tests to assess your overall health and determine if you're a candidate for gene therapy.
2. Stem cell collection. To collect blood-forming stem cells, you will be given a medication that helps move stem cells from the bone marrow into the bloodstream. Blood is drawn from a vein with a catheter and circulated through a machine that removes the blood stem cells. The other parts of the blood circulate back into the body through another catheter.
3. Gene modification. In a laboratory, medical scientists will add a functional gene to your collected blood stem cells or edit the existing genes in those stem cells. This part of the process can take several months or longer.
4. Myeloablative conditioning. To make room for the modified stem cells, you will receive high doses of chemotherapy to destroy existing bone marrow. Some people are able to undergo reduced-intensity conditioning (RIC), which involves lower doses of chemotherapy and destroys less bone marrow.
5. Infusion of modified cells. The modified blood stem cells are returned to your body through an IV infusion (similar to a blood transfusion).
6. Recovery. The recovery process for gene therapy is long. A person will be in the hospital for up to six weeks. It will take about four weeks for the transplanted cells to begin producing new blood cells. A person will require long-term monitoring for disease recurrence and side effects. During recovery, your healthcare team will closely monitor your blood cell counts and watch for complications.

Keep in mind that these are very simplified explanations of complex medical technologies. For detailed explanations on these therapies and how they work, your healthcare team will be your best source of information.