While gene therapy holds promise as a potential treatment for many patients, there are still challenges in its use for all. We have seen serious side effects in individuals with certain genetic variations who have received microdystrophin transgenes. This is due to the possibility of the body recognizing the newly produced microdystrophin transgene as a foreign protein. In those instances, the body’s immune system can attack cells expressing the microdystrophin protein as if it were a harmful viral or bacterial protein.
It appears that this type of immune response, where the body recognizes the new microdystrophin protein as foreign, is limited to people with specific genetic variants. Even though people with Duchenne are not producing functional dystrophin proteins, the cells typically try to produce some dystrophin or at least portions of dystrophin protein. The dystrophin protein produced from Duchenne variants are non-functional and usually destroyed by natural processes in the cell. For a large number of individuals with Duchenne, their body will be used to seeing portions of the dystrophin protein even if it is non-functional. However, for others their bodies may have never seen any parts of the dystrophin protein. In those cases, when an individual has never seen any parts of the dystrophin protein, the body may consider any new dystrophin or microdystrophin protein as foreign. Because of the design of the microdystrophins, certain genetic variants seem more likely to have this kind of reaction. Research is still ongoing to determine which genetic variants have a high risk for an immune response. Unlike immune responses to the viral vector, AAV, used in delivery, these transgene immune responses typically arise around 4-6 weeks after receiving the gene therapy. The transgene immune response can cause serious side effects such as muscle or heart inflammation.
An additional challenge with micro-dystrophin gene replacement is an immune response to the newly produced micro-dystrophin protein. In a few of the micro-dystrophin gene therapy trials, it was reported that some individuals had an immune response to the newly produced micro-dystrophin around a month following dosing (5 patients to-date). In these instances, it is hypothesized that the body may be recognizing the parts of the new micro-dystrophin protein as foreign, so the immune system treats it like other foreign proteins and will target the cells with the micro-dystrophin.
When we talk about Duchenne, we typically say that an individual isn’t producing any dystrophin. While they may not have any functional dystrophin in their cells, their bodies’ natural cellular process is still trying to turn the coding instructions in the gene from DNA into proteins. For instance, if a person has a deletion starting at exon 30, the molecular machinery that produces proteins will still have the instructions to begin producing a dystrophin protein, even if the dystrophin ultimately is non-functional and destroyed by other cellular processes. For that individual their body would have ‘seen’ some amount of dystrophin protein and recognize it as ‘self’ rather than as foreign. For individuals with certain variants, the portions of the micro-dystrophin protein that are being introduced in gene replacement appear to the body’s immune system as foreign rather than ‘self’. This can trigger an immune response that targets cells expressing this protein that the body now considers foreign. This can lead to serious side effects such as heart or muscle inflammation.
Work has been ongoing in a collaboration between members of the National Institute of Health (NIH) and companies developing micro-dystrophin gene therapy to better understand who is at risk, what regions of the dystrophin protein are most likely to cause an immune response and how we can mitigate this response.
