• About genetic disease
  • What is investigational gene therapy?
  • What is gene therapy meant to do?
  • How investigational therapies are studied
  • About genetic disease

    Genes: the body’s instruction manual

    The human body is made up of trillions of cells. At the center of each cell is the nucleus, which contains all of the instructions the body needs to function.

    These instructions are stored on chromosomes, which are made up of DNA (deoxyribonucleic acid). DNA is organized into genes, which provide instructions to make proteins—molecules that build, regulate, and maintain the body. Clotting factors are an example of proteins.

    Human body made up of cells Center of each cell is the nucleus containing instructions for body Body’s instructions are stored on chromosomes, made of DNA DNA organized into genes Right arrow Protein
    Human body made up of cells Center of each cell is the nucleus containing instructions for body Body’s instructions are stored on chromosomes, made of DNA DNA organized into genes Right arrow Protein

    Another way to think about this is like a reference library.

    Library building as a nucleus Books as chromosomes Open book with instructions Right arrow Book with lighbulb as a protein

    The library (nucleus) contains a bunch of “how to” encyclopedias (chromosomes) that are written in their own special alphabet (DNA). The encyclopedias (chromosomes) are organized into specific chapters (genes), which provide the instructions the body needs to build proteins.

    What is investigational gene therapy?

    Introduction to gene therapy research

    Gene therapy is a potential approach to treating or preventing genetic diseases. The goal of gene therapy is to address a genetic disease at its source—the gene. This can be done by modifying (changing) genes or creating new functional genes in a laboratory and delivering them to specific cells in the body.

    50 years of research

    Scientists have been investigating gene therapy for more than 50 years, and the science around gene therapy continues to evolve. To date, more than 2,600 gene therapy clinical trials are planned, ongoing, or have been completed for different genetic diseases.

    Gene therapy is the approach being most broadly investigated for use in hemophilia. This approach introduces a new functional copy of a gene with the aim of restoring or enhancing its original function. It is sometimes referred to as gene augmentation, gene transfer, or gene replacement.

    Gene therapy

    Creating new functional genes in a laboratory and delivering them to specific cells in the body

    Vector carrying new functional gene into target cell Vector carrying new functional gene into target cell

    What is investigational gene therapy meant to do?

    Step by step

    The overall goal of investigational gene therapy is to deliver a functional gene to a specific, or target, cell.

    Instruction manual (functional gene) Right arrow Package for delivery (vector) Right arrow Placed into mailbox for delivery (body) Right arrow Delivered to correct address (target cell)

    Think of the functional gene as the instruction manual that tells the body how to make a desired protein.

    Once a functional gene is created, there must be a way to deliver it to the right address, or target cells. The functional gene can be inserted into a viral-based shell, creating a delivery package known as a vector.

    The vector’s sole purpose is to deliver the functional gene to the correct target cell type—just like an envelope that ensures the instruction manual gets to the right address. The envelope (vector) is then placed into the mailbox (body) and mailed to the correct address (target cell type) to deliver the instruction manual (functional gene).

    Vectors are chosen because they have an affinity, or preference, for a specific cell type or types, allowing the functional gene to get to the right place. They’re sort of like a pre-addressed envelope that can only be sent to a particular address.

    How investigational therapies are studied

    Safety and well-being of patients are top priorities

    Following many years of initial (preclinical) research, which includes laboratory, manufacturing, and animal studies, investigational new therapies may then be reviewed and approved by the FDA for research studies in humans, known as clinical trials. Clinical trials include multiple phases and extensive review of data to—first and foremost—ensure the safety of patients.

    Drug discovery and clinical trial timeline Drug discovery and clinical trial timeline
    STEPS IN DRUG DEVELOPMENT
    APPROXIMATE LENGTH OF TIME
    Drug discovery & preclinical research (laboratory or animal studies)
    1 to 6 years
    Clinical trials: Phases 1, 2, and 3 (human studies)
    6 to 11 years
    FDA review
    1/2 to 2 years
    Continued research and monitoring
    Indefinite

    Results from clinical trials provide insights into the safety, effectiveness, and appropriate use of the gene therapy being studied.

    Potential risks of gene therapy

    As with any new treatment being researched, there is the potential for unintended effects. To help identify these risks, gene therapies are studied in clinical trials under controlled conditions. While the safety of investigational gene therapy is still being studied, research to date has helped scientists learn important lessons.

    Potential risks identified in gene therapy research so far include the following:

    • The body’s immune system could respond in unintended ways.

      The job of the immune system is to defend against outside pathogens—things, such as viruses, from outside the body that could cause harm or sickness when inside the body. While this defense mechanism is normal and expected, it could cause the immune system to resist or attempt to fight off the gene therapy. This is because the immune system may see the vector, acting as the delivery vehicle for gene therapy, as something that isn’t supposed to be there, an “invader.” This may lead to immune responses in the body, such as:

      • Swelling of the liver, which, if not controlled, could lead to a decrease or loss of the factor protein made from investigational gene therapy. Treatment, such as a short course of steroids, may be required to calm the immune system.
      • The development of antibodies in response to AAV gene therapy, which could make someone ineligible for AAV gene therapy research and potential future treatments. This is because the antibodies would recognize the previously identified AAV gene therapy and escort it out of the body.
      • The development of antibodies against FVIII or FIX (also called inhibitors), which would limit the ability of gene therapy to work as desired.
      • Allergic reactions ranging from mild to severe
    • Other potential risks could occur related to the gene transfer itself

      • The functional gene carried by a vector may be delivered to the wrong cells. While vectors tend to be specific in the cells they target, there is still a risk that vectors could find their way into unintended cells. This could damage those cells or cause inappropriate cell growth, leading to tumors or cancer.
      • Once the AAV vector has placed the functional gene inside the nucleus, the vector’s empty shell (the “envelope”) is removed (or shed) from the body. This “vector shedding” occurs in fluids such as urine, semen, or saliva. While rare, this could lead to the formation of antibodies to the AAV vector in people who come in contact with these fluids. This could unintentionally make someone ineligible for AAV gene therapy in the future.

    Studies are ongoing and participants continue to be followed. Additional risks may be identified in the future.

    Learning more

    If you're interested in learning more about gene therapy clinical trials for hemophilia, speak with your physician and visit ClinicalTrials.gov.