Gene therapy is a treatment option for adults 18 years of age or older. It is important to understand how it works so that you can plan for your future. It is also important to understand that the gene is not edited or fixed. This means the gene for hemophilia can still be passed down to offspring. The National Bleeding Disorders Foundation (NBDF), has many resources that can help you understand gene therapy. This video is a great starting point on your path of learning about gene therapy.

What is this treatment for? 
Gene therapy can be used to treat many different disorders and diseases. Gene therapy is a treatment that provides your body with new copies of the genes that are not working properly. For hemophilia A or B, gene therapy can provide the instructions to help the body produce the missing factor it needs to enable blood clotting.2 Gene therapy is a treatment that could allow someone with hemophilia to be able to stop or use less of their current treatment. 
How does this treatment work in the body?

Our body contains instructions, called genes, that tell the body how to do things like grow or how to make proteins. Proteins are the building blocks for everything that happens in the body. Some diseases or disorders, such as hemophilia or other bleeding disorders, happen when proteins are not made or do not work correctly. This treatment works to provide the body with a copy of a working gene. For hemophilia A or B, that is the factor VIII (8) or IX (9) protein.    

To get a new working gene into the body, it must be protected so that the gene does not get broken down before it can start working. The gene is put into a package called a vector. The vectors used in gene therapy are viruses.2 The viruses used for gene therapy are changed so that they cannot make you sick. Instead, the virus protects the gene so that it can travel through the body and get into the liver cell. The virus used in gene therapy for hemophilia is the adeno-associated virus (AAV).     

After receiving the infusion of gene therapy, your body will have the instructions for making factor. Gene therapy targets the liver cells which is where factor is produced.2 The instructions (genes) are released from the virus into the liver cells, where they tell the liver cells to produce factor.2 This factor protein travels in the bloodstream and will allow your body to make a stable blood clot. It is important to work with your health care provider to determine if this treatment is right for you. Here is a list of questions about gene therapy that you can ask your health care provider about to learn more.

How is this treatment given?
During gene therapy, adeno-associated viruses (AAV) containing the correct instructions (genes) for making factor are put into the body. This is done using a needle that goes into your vein (infusion). The process takes one to two hours. This is a one-time treatment and is done on site at a medical facility like a Hemophilia Treatment Center (HTC). You will have extra follow-up visits for monitoring, but the infusion only happens once. This is quite different than the other current therapies for hemophilia which require daily, weekly, or monthly treatments. It is important to understand that once gene therapy is given, it cannot be undone. At this time, if it stops working or does not work at all, it cannot be done again.  
How much of the treatment is normally given?
The dosage for gene therapy will differ based on the product, the patient’s weight, and other things. Your HTC or health care provider will help you learn about the dosage. Typically, these are extremely high doses that contain trillions of gene particles. 
Who can use this treatment?
Gene therapy is approved for healthy adult males, at least 18 years old with moderately severe to severe hemophilia. Gene therapy is not a treatment option for people with an inhibitor to factor VIII (8) or IX (9), which means that the body attacks the factor protein. There are other disorders that might prevent you from receiving gene therapy. These include liver diseases like hepatitis or health issues that may not be related to your bleeding disorder like heart disease5. It is important to work with your health care provider to determine if this treatment is best for you.  
What are the benefits? 
Gene therapy is a treatment that provides your body with instructions on how to make its own factor. This one-time treatment will hopefully reduce or do away with factor infusions. This treatment should also keep you from having a spontaneous bleed, which means that you could have a bleeding episode without an injury. This type of treatment should keep your factor levels stable so that you don’t have “peaks and troughs” that you do with regular treatment options. The hope is that you will have a better quality of life.
What are the limitations, risks, or unknowns with gene therapy?

While gene therapy is promising, there are many risks that you need to understand. Unlike other treatments for bleeding disorders, gene therapy works differently in every individual, so it is hard to know if it will work for you. The vector can show up in other cells in the body that are not the target liver cells. There is a chance that the genes can change your genetic information if they are inserted into the wrong area.3 Because this is a new therapy, the long-term side effects are unknown. This is a treatment that cannot be undone. This is also a very high-cost treatment and there is uncertainty around what insurance reimbursement might look like. Here is some more information on known risks:   

  • One-time only treatment

    • Once you have received gene therapy using an adeno-associated virus (AAV), you will not be able to have another treatment of gene therapy using this same virus, even if your first gene therapy treatment does not work for you or stops working. The reason gene therapy can be used only one time is that your body will now recognize the virus and attack it if it sees this virus again. When your body attacks the virus, it will cause the virus to be unable to deliver the gene to the liver. If the gene cannot reach the liver cells, it will be unable to provide the instructions needed to make factor.

  • Potential damage to the liver

    • Once you have gene therapy, you will need to be closely monitored by your health care provider. You will have your blood checked every week for the first three months after your treatment. These weekly blood tests are done to check for any liver damage that may be caused by the gene therapy and to check factor levels to see how well the gene therapy is working.6 Treatment is given to patients with test results that show stress on the liver due to the gene therapy.

  • Potential for an inflammatory response

    • Your body may react to the gene therapy causing an inflammatory response which is your body’s process of fighting against things that could cause harm like infections or injuries. Due to the high dose of viral particles needed to help your body produce factor you may need extra treatment with high dose steroids for a few weeks or months.3 Left untreated, this inflammatory response may be dangerous and may lead to a decrease in the production of factor.

  • Potential for liver cancer

    • There is a small possibility that the DNA used for your gene therapy treatment will go to areas of the body where it does not belong. The result of this can be liver cancer in some cases.3 If you have an increased risk for liver cancer (including cirrhosis, hepatitis B or C, non-alcoholic fatty liver disease, or chronic alcohol consumption), you should receive annual abdominal ultrasound screenings and blood tests to check your liver the first five years after treatment.  

If you want more information about gene therapy, please go to Future Therapies | Frequently Asked Questions | National Hemophilia Foundation 

References:

  1. Hemgenix (etranacogene dezaparvovec) dosing, indications, interactions, adverse effects, and more. (2023). https://reference.medscape.com/drug/hemgenix-etranacogene-dezaparvovec-4000307   

  2. Doshi, B. S., & Arruda, V. R. (2018). Gene therapy for hemophilia: what does the future hold? Therapeutic Advances in Hematology, 9(9), 273–293. https://doi.org/10.1177/2040620718791933   

  3. Monahan, P. E., Negrier, C., Tarantino, M. D., Valentino, L. A., & Mingozzi, F. (2021). Emerging immunogenicity and genotoxicity considerations of Adeno-Associated virus vector gene therapy for hemophilia. Journal of Clinical Medicine, 10(11), 2471. https://doi.org/10.3390/jcm10112471   

  4. Nathwani, A. C. (2019). Gene therapy for hemophilia. Hematology, 2019(1), 1–8. https://doi.org/10.1182/hematology.2019000007   

  5. Krumb, E., Lambert, C., & Hermans, C. (2021). Patient selection for hemophilia gene therapy: Real‐life data from a single center. Research and Practice in Thrombosis and Haemostasis, 5(3), 390–394. https://doi.org/10.1002/rth2.12494   

  6. Research Human Gene Therapy for Hemophilia. U.S. Food And Drug Administration. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/human-gene-therapy-hemophilia   

  7. Roctavian (valoctocogene roxaparvovec) dosing, indications, interactions, adverse effects, and more. (n.d.). https://reference.medscape.com/drug/roctavian-valoctocogene-roxaparvovec-