An overview of gene therapy for inherited blood disorders

Sickle cell disease and beta thalassemia are two inherited blood disorders that affect the production of hemoglobin. Hemoglobin is a protein that is one of the main components of red blood cells. This protein enables red blood cells to carry oxygen to different tissues throughout the body. It also enables red blood cells to carry carbon dioxide to the lungs so that it can be exhaled from the body.

Mutations to the HBB gene

Both conditions are caused by mutations to a gene called HBB. A gene is a segment of DNA. Many genes function as instructions for making specific proteins. HBB contains instructions for making beta-globin, a subunit or component of hemoglobin.

When a person has sickle cell disease, they have a mutation in the HBB gene that creates abnormal beta-globin. This results in abnormal red blood cells, which are called sickle cells because of their crescent or sickle-like shape. Sickle cells breakdown in the bloodstream, causing low levels of red blood cells (anemia). Sickle cells can also get stuck in small blood vessels, causing pain and organ damage.

With beta thalassemia, a person has a different type of mutation to the HBB gene. This variation interferes with the body’s ability to produce beta-globin. This results in low levels of hemoglobin. Anemia is the most common symptom and can range from mild to severe. Severe beta-thalassemia can cause life-threatening complications.

Gene therapy is a new and emerging treatment option

While these are different conditions that require different therapies, both sickle cell disease and beta thalassemia may be treated with bone marrow transplants. Also called a stem cell transplant, this is an intense procedure that requires a matched donor, but it has the potential to cure these conditions.

Some cases may also be treated with gene therapy, which is a new and emerging treatment option that is also a potential cure.

If you or a loved one is living with one of these conditions and considering gene therapy, here is some background on what to expect.

How does gene therapy work?

Gene therapy addresses the genetic mutations that are the underlying cause of sickle cell disease and beta thalassemia. This will increase the amount of healthy hemoglobin and decrease the amount of abnormal hemoglobin. There are two main types of gene therapy that are currently being used, gene addition and gene editing.

Both methods begin with the collection of blood stem cells (immature cells that can develop into different types of blood cells). The collected stem cells are sent to a lab where one of several processes will be used to alter the gene:

• Gene addition. In this process, a normal HBB gene is added to the collected stem cells. If successful, this will allow the stem cells to produce normal hemoglobin.
• Gene editing. This process makes an alteration 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.

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

What steps are involved in receiving gene therapy?

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

1. Evaluation. Your healthcare team will perform exams and tests to determine if you're a candidate for gene therapy and assess your overall health.
2. Stem cell collection. You will be given medications that help move these blood-forming stem cells from the bone marrow into your bloodstream, where they can be collected using a machine. This process is called apheresis.
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. Conditioning. You will need to receive high-dose chemotherapy to make space in your bone marrow for the modified stem cells. This will be one of the most challenging parts of the treatment process, as chemotherapy causes significant side effects and essentially deactivates the immune system.
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.

A healthcare team will be your best source of information for more details about the individual steps in gene therapy.