Haemevolution

Are You a Healthcare Professional?

This European website, initiated and developed by CSL Behring, has two separate sections with the aim to provide information on haemophilia for an international audience, either to European healthcare professionals or to the general public.*

Yes, I am a healthcare professional*

Enter Site

No, I am not a healthcare professional

Enter Site

*CSL Behring is legally obliged to restrict some areas of the website to healthcare professionals only. By clicking “Yes, I am a Healthcare Professional”, you confirm this statement is true and you accept all liability related to the above. If you are not a healthcare professional you can visit the section of this website for the general public.

How Does Gene Therapy Work for Haemophilia?

All investigated gene therapies for haemophilia, to date, have used an in vivo AAV vector strategy,1,2 which has five key steps: from vector engineering to transgene delivery.

  • Adeno-Associated Viral (AAV) Vector Capsid

    AAV Vector Capsid

    1. Selecting the Adeno-Associated Viral (AAV) Vector Capsid

    In order to deliver a therapeutic gene - or transgene - it must be packaged into a delivery vehicle. AAVs are viruses and the surface of the virus is called a capsid. The capsid is like a shell which protects its genetic blueprint within. AAVs have evolved many kinds of capsids, so they can enter different types of cells. One of the most important factors for choosing the AAV vector depends on which cells are the target of the gene therapy. For haemophilia, the liver is the target, as that is where the body produces clotting factors.3

  • Functional Gene to Empty Shell

    Functional Gene to Empty Shell

    2. Production of the Recombinant AAV (rAAV) Vector

    The next step is to engineer a recombinant AAV (rAAV). Recombinant is a word meaning ‘joining two things’. In other words, in gene therapy the rAAV combines components from human (the target) and AAV (the delivery vehicle). The rAAV is made by removing the viral genetic blueprint, to make an empty shell, and inserting the factor VIII or IX transgene information.1,4 The rAAV has now been loaded with instructions of how to make healthy factor proteins.

  • AAV Vector

    AAV Vector

    3. Delivery of the Transgene

    AAV vector gene therapies can be delivered by an injection to the veins, muscles or directly to certain organs.4 Because the liver is the location of clotting factor production,3 for haemophilia, gene therapy delivered as an injection to the veins is optimal in order to reach the liver.4,5

  • Liver cell with nucleus.

    Liver cell with nucleus.

    4. Vector Makes Contact With the Cell

    Once infused in the body, the vector will be able to bind to hepatocytes (liver cells) using liver-specific receptors on the surface of its capsid. Once attached, the transgene is brought into the cell.6 After entering the liver cell, the transgene enters the centre of the cell, the nucleus. This is the final destination of the transgene, where it is expected to stay in the nucleus of the cell as a separate genetic blueprint, called an episome. This episome remains independent from the cell’s own genetic blueprint but remains long-term so the cell is able to continue producing functional proteins.6

  • Human

    5. Therapeutic Outcome

    After a liver cell makes successful contact with a vector, the cell is now able to use the genetic blueprints of factor VIII or IX to create its own functional clotting factor proteins long-term that it was unable to do before.6

Previous

Gene Therapy

Discover the advances scientists have made over the last 50 years, making genetic therapies possible for many patients with genetic diseases and chronic conditions.

Next

Preparing for Gene Therapy

Some aspects to think about when considering gene therapy.

References

  1. Doshi BS, Arruda VR. Gene therapy for hemophilia: what does the future hold? Ther Adv Hematol. 2018;9(9):273-293.
  2. Nathwani AC. Gene therapy for hemophilia. Hematology Am Soc Hematol Educ Program. 2019;2019(1):1-8.
  3. Heinz S, Braspenning J. Measurement of blood coagulation factor synthesis in cultures of human hepatocytes. Methods Mol Biol. 2015;1250:309-16.
  4. Naso MF, Tomkowicz B, Perry WL III, Strohl WR. Adeno-associated virus AAV as a vector for gene therapy. BioDrugs. 2017;31:317-334.
  5. Nathwani AC, Reiss UM, Tuddenham EGD, et al. Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371:1994-2004.
  6. Wang D, Tai PW, Gao G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov. 2019;18(5):358-378.
  7. Perrin GQ, Herzog RW, Markusic DM. Update on clinical gene therapy for hemophilia. Blood. 2019;133(5):407-414.
  8. Arruda VR, Doshi BS. Gene therapy for hemophilia: facts and quandaries in the 21st century. Med J Hematol Infect Dis. 2020;12(1):e2020069.
  9. Arruda V, Stedman H, Jian H, et al. Correction of hemophilia B phenotype by novel method of regional intravenous delivery of AAV vector to skeletal muscle of hemophilia B dogs. Mol Ther. 2005;11:S233.
  10. Nathwani AC, Tuddenham EGD, Rangarajan S, et al. Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. New Engl J Med. 2011;365(25):2357-2365.
  11. Nathwani AC, Reiss U, Tuddenham EGD, at al. Adeno-associated mediated gene transfer for hemophilia B: 8 year follow up and impact of removing "empty viral particles" on safety and efficacy of gene transfer. Blood 2018;132(Suppl 1):491.
  12. High KA, Roncarolo MG. Gene therapy. N Engl J Med. 2019;381(5):455-464.
  13. Food and Drug Administration (FDA) Cellular, Tissue, and Gene Therapies Advisory Committee Meeting #70. Toxicity risks of adeno-associated virus (AAV) vectors for gene therapy (GT). Published September 2021. https://www.fda.gov/media/151969/download Accessed July 14, 2023.