Because Adeno-associated virus or AAV is a virus it will cause your body’s immune system to react like it would when any foreign DNA is introduced to your body. Because your immune system has multiple ways to fight infections these responses can occur at different times following delivery. The impact on a person’s body varies depending on the type of immune response. A person’s innate immune response is the first wave of fighting off a viral infection and can lead to reactions such as complement activation. Symptoms of an innate immune response to AAV gene therapy include fever and vomiting and typically occur within a few days of receiving the gene therapy. The acquired immune response is how the body produces antibodies to a virus it has been previously exposed to. This can be a more delayed response typically occurring about one month after receiving the gene therapy. The acquired immune response can be triggered by the virus or the transgene and can lead to serious side effects such as inflammation of the muscles.
Clinical trials of gene therapy in Duchenne have reported a number of serious or life threatening side effects. These include platelet cells being depleted which could affect blood clotting, cells in the body being attacked, and even death through cardiogenic shock or the heart being put under too much stress from the immune response.
Reducing immune responses may be possible through the use of immunosuppressive drugs which already exist or by developing viral vectors that cause less of an immune response. Another potential strategy to avoid the immune response to the virus is development of non-viral delivery systems, which could eventually replace viruses as the delivery vector for gene therapy.
Even though adeno-associated viruses (AAVs) used for gene therapy are not known to cause disease in humans, your body will still recognize the virus as a foreign particle and mount an immune response. This is why many gene therapy protocols include an increased dose of corticosteroids at the time of delivery and for the following one to two months; corticosteroids suppress the immune system and may help limit these events.
A serious immune response can happen even if you have never been exposed to AAV and don’t have antibodies. This is due to what is called the innate immune response, which is the body’s first wave of protection against infection.
Typically people producing significant antibodies to AAV are excluded from receiving gene therapy as discussed in AAV Immune Challenges.
In order to lower the risk of an immune response to AAV, many researchers are exploring the use of immunosuppressive drugs to temporarily lower the immune response. There also may be non-AAV methods of delivering transgenes that don’t trigger the same immune response, though those strategies are still in early development.
These various strategies, such as immune suppression, may have their own risks that would need to be evaluated for overall risk/benefit for an individual.
