A guide to discussing gene therapy for sickle cell disease

Sickle cell disease is a genetic disorder caused by mutations or variations in the HBB gene, a segment of DNA that contains instructions for making a substance called beta-globin. These mutations result in the production of abnormal beta-globin.

Beta-globin is one of the main components of hemoglobin, an iron-rich protein found in red blood cells that transports oxygen throughout the body.

Red blood cells are normally round and smooth and move easily through blood vessels. The abnormal beta-globin associated with sickle cell disease causes red blood cells to have a crescent or sickle shape.

These sickle cells die off easily, leading to anemia, or low numbers of red blood cells. Sickle cells can also become stuck in blood vessels, causing vaso-occlusive crisis (VOC), episodes where blood flow is blocked. This prevents oxygen from reaching cells and tissues, which can cause severe pain and potentially lead to severe complications, including organ damage.

For many years, the only potential cure for sickle cell disease was a stem cell transplant, also known as a bone marrow transplant. In recent years, gene therapies have emerged as potentially curative therapies for sickle cell disease.

How does gene therapy treat sickle cell disease?

As the name implies, gene therapies target mutations in the HBB gene. In the simplest terms, these are therapies that aim to correct the mutations that lead to the formation of the abnormal beta-globin that creates sickle cells.

But gene therapy is not a simple fix. This is a long and multi-step process that requires a lot from the person being treated and the caregivers who will help them through the process, should they decide to pursue gene therapy.

How gene therapies work (in simple terms):

• Blood stem cells are collected from the person being treated. These are immature blood cells that can develop into different types of blood cells, including red blood cells, platelets, and white blood cells.
• The collected blood stem cells are modified in a lab to correct the HBB variation. These modified blood stem cells will be transplanted back to the person being treated.
• To prepare for the transplant, a person will need to undergo intensive chemotherapy to destroy existing bone marrow. This part of treatment is called conditioning. It kills off cells that carry the variant HBB gene. It also creates space for the modified stem cells to be reintroduced.

A person will need to stay at a hospital for a month or longer, and the recovery process can take up to a year. Gene therapy is also expensive.

What should you discuss with your healthcare team?

If you or a loved one is living with sickle cell disease and interested in exploring gene therapy, your best source of information will be your healthcare team. A healthcare team can fully explain the process, the risks, the potential benefits, and what will be required from the person being treated as well as their caregivers.

If you are preparing to talk to a healthcare provider, here is a list of topics to help you get started:

• The age and overall health of the person considering gene therapy.
• The severity of sickle cell symptoms and the risk of complications from sickle cell disease.
• How well the current treatment for sickle cell disease is working, and what other treatment options are available if you need to change treatment.
• The potential for long-term side effects from intensive chemotherapy, including damage to organs, compromised immunity, and infertility, and how these risks compare to the potential benefits of gene therapy.
• The recovery process, including the expected length of the hospital stay, how much time away from work or school will be required, the care that a person will need during recovery, and how often they will need follow-up appointments after treatment.
• The financial considerations, including insurance coverage, the out-of-pocket expenses, and the indirect costs (such as time away from work for the person being treated or family members).

Again, your best source of information for these questions or any others that you have will be your healthcare providers.