Adeno-associated virus or AAV exists in nature, though it has not been found to be disease causing in humans. Because it does exist in nature it is possible for an individual to have been exposed to AAV. If a person has been exposed their body will treat AAV like any foreign virus and their immune system may begin to produce antibodies to prevent re-infection.
Exposure to AAV in the environment may lead to the production of antibodies, this is often referred to as a patient having pre-existing antibodies. If a person is producing a high number of antibodies to AAV they may not be able to receive gene therapy, as the immune response to AAV could prevent the gene therapy from being delivered to the muscles or cause a harmful response to the body.
Antibody levels are assessed through a titer test. This is a test that can be used to tell how many antibodies an individual is producing. Typically there is a threshold of how many antibodies a person can have and still safely receive therapy, which is influenced by a number of different factors. Individuals receiving gene therapy must have antibodies below the threshold deemed as safe. If titer levels are above the threshold there could be an immune response that limits effectiveness of delivery or even puts the person at risk of a potentially dangerous immune response. For those with pre-existing antibodies, immune suppression strategies could be developed to temporarily lower the antibodies to a safe level for dosing, though this may be more challenging for redosing.
Re-dosing, or receiving a second dose of gene therapy, is a challenge in gene therapy because an individual is exposed to up to a quadrillion virus particles with a typical gene therapy infusion. This is well beyond the number of virus particles you are exposed to if you were infected naturally. Once someone has been exposed to a high dose of virus, the immune system will work to produce antibodies to protect them from what it recognizes as future infections.
The vector that is typically used in Duchenne gene therapies is Adeno-associated virus (AAV). AAVs are not known to cause disease in humans but do exist in nature, because of this it is possible for a human to have been exposed to AAV. If that happens, that individual’s immune system will treat that AAV like any other foreign virus and start to produce antibodies to help prevent future infections. This creates challenges for gene therapy in Duchenne.
The term pre-existing antibodies refers to a person who has been exposed to AAV at some point in their life and is now producing antibodies. If a person has a high number of antibodies to AAV they are typically ineligible for receiving a therapy that uses that AAV. This is because those antibodies can neutralize the virus and render the therapy ineffective or trigger a potentially dangerous immune response.
Antibody levels are screened through a titer test, which helps to show how many antibodies a person is producing to a certain virus. You may see numbers such as needing a <1:400 ratio for the titer threshold. When you hear the term ‘high titer’, that means that a person has a large amount of antibodies to a virus, so even when their blood (which contains the antibodies) has been diluted many times there are still enough antibodies present to bind a virus.
Let’s break down what this means:
There are different ways investigators are thinking about overcoming these immune challenges to pre-existing antibodies:
A major challenge remaining is how to re-dose people. Unlike an exposure to AAV in nature, where a person may develop some small number of antibodies, a gene therapy treatment is delivering trillions of copies of a virus into the body. This will result in the production of a significant amount of antibodies that may not come down to a level that allows for re-delivery of a gene therapy product with the same viral vector.
