Speakers from the event address fundamental questions about the immune system's response to AAV gene therapies, how these responses can affect treatment outcomes, and the methods being developed to manage immune reactions.
Listen to Quick Takes from experts in the community on the following questions (Time: 25 min):
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Put simply, what does the immune system have to do with a gene therapy?
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What is the most common virus used in gene therapy clinical studies?
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What does an patient or caregiver need to understand about immune responses to an AAV vector gene therapy when considering potential treatments?
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What would qualify or exclude someone from a clinical study?
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How does the route of administration in clinical studies impact immune responses?
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How does the maternal immune environment play a role in treating newborns?
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How can immune responses be managed?
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Do immune modulation protocols vary by product?
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How does the immune response to AAV impact treatment outcomes?
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What is something to be excited for in this field currently?
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How does the quality of the AAV product play into the immune response?
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How are animals used in pre-clinical research to better understand immune responses to AAV gene therapy?
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What is the utility of using larger animal species and where do they fall short in trying to study the immune response to gene therapy?
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Key Takeaways
For the Patient or Caregiver
Pre-existing antibodies determine eligibility - One of the most important criteria for receiving AAV gene therapy is whether a patient has pre-existing antibodies against the specific AAV vector being used. Different tests are used to measure these antibodies, with each test specific to the product being administered.
Antibody thresholds vary by product - The acceptable level of antibodies (titer) varies depending on the specific gene therapy product. Product Developers determine thresholds to ensure the therapy remains safe and effective. Different organs have different tolerances for antibody levels, with the liver being more permissive than the muscle, heart, or brain. Example thresholds of approved therapies include:
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Zolgensma (for SMA): Has a very low antibody threshold of 1:50, meaning only patients with minimal antibodies qualify.
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Elevidys (for Duchenne muscular dystrophy): Allows a higher antibody threshold, making more patients eligible.
Switching between AAV types won’t avoid an immune response - A patient who develops antibodies to one AAV type cannot simply switch to another AAV vector to bypass immunity, as the immune response is often cross-reactive across different AAV products.
Immune Responses
Managing immune responses to AAV gene therapy
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Higher-dose AAV gene therapies are reaching the maximum tolerable level for the body, making immune response management crucial.
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Initial immune suppression strategies (e.g., glucocorticoids) have been effective for lower doses, particularly in liver-targeting therapies. Glucocorticoids are used to suppress the activity of immune cells.
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Higher-dose therapies (e.g., for brain-targeting treatments) reveal new immune challenges, including rapid antibody formation within 48 hours.
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Pre-existing antibodies and the immune system’s first line of defense can pose safety risks and must be managed carefully.
Strategies for immune modulation
Immune modulation is the process of altering or adjusting the immune system's response. Some examples include:
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Existing drugs can block B cells from producing antibodies, allowing the vector to work effectively for weeks before the immune system reacts.
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New strategies aim to inhibit only AAV-specific antibodies while preserving general immunity, minimizing the risk of infections.
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Immune suppression typically lasts only about a month post-treatment, but long-term monitoring is needed for potential late immune effects.
Protocols may vary - There is no universal immune suppression protocol; strategies vary by therapy and patient characteristics. Some therapies rely solely on glucocorticoids, while others use pre-screening methods to identify patients at higher risk for immune reactions. Future strategies may involve tailoring immune modulation based on genetic susceptibility to adverse immune responses.
Impact on treatment outcomes
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Strong antibody responses to AAV can last for decades, as seen in patients still antibody-positive 25 years after initial exposure.
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Long-lasting immunity presents a challenge for redosing, requiring new approaches to suppress or reset the immune response.
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Researchers are exploring immune-based strategies to eliminate antibody-producing cells and allow for potential retreatment.
Future directions - Research is focused on modifying AAV capsids to reduce immunogenicity and improve patient tolerance. Advancements in immune modulation strategies aim to fine-tune or eliminate unwanted immune responses, making redosing feasible in the future.
Role of the Immune System
The immune system plays a crucial role in gene therapy, similar to how it responds to vaccines and viral infections. In AAV-based gene therapy, the immune system recognizes the virus’s protein coat and produces antibodies. These antibodies can persist for years, preventing future dosing with the same therapy. Some patients have pre-existing immunity to AAV, which can make them ineligible for treatment.
The most frequently used virus in gene therapy clinical studies is adeno-associated virus (AAV). AAV is a small, single-stranded virus that naturally occurs in more than 50% of adults due to environmental exposure. AAV does not cause disease on its own; it typically coexists with other viruses like adenovirus or herpesvirus. Because AAV is not disease causing, it is widely used as a gene therapy vector to deliver therapeutic genes into cells.
Role of Preclinical Studies
Small animal models - Mice are commonly used due to their well-characterized immune system and the ability to manipulate their genes to study immune responses. While mice do not perfectly replicate human immunity, they offer a powerful tool when engineered with human-specific receptors to improve targeting.
Large animal models - Primates have evolved to tolerate viral infections, leading to a lower magnitude of immune response compared to humans. Domesticated animals like cats and dogs exhibit immune responses more similar to humans but are harder to use for disease modeling.
Future directions - A promising approach involves integrating human-specific receptors into mouse models, allowing for more precise study of gene therapy vectors. Rodent models remain valuable due to their flexibility in replicating various genetic disorders (dominant and recessive).
Continuing the Journey
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