A Genethon team, working as part of an international collaboration, published the results of their work in Nature Medicine on June 1, 2020, opening up new perspectives for gene therapy. Using the IdeS enzyme, these researchers succeeded in inhibiting the immune response to AAV, which is caused by antibodies present as a result of natural immunity or following gene therapy.
Gene therapy consists of injecting a therapeutic gene into an organism using a vector, a “means of transport” able to cross all biological barriers through the cell and into the nucleus. The most commonly used vectors are derived from viruses, such as AAVs. In many cases, once in contact with this virus, the body develops immunoglobulins (IgG) known to be neutralizing, i.e. specific antibodies that inhibit AAVs and make gene therapy ineffective.
To lift the immune barrier and treat a greater number of patients, the team headed by Giuseppe Ronzitti at Genethon, in collaboration with teams from the Cordeliers Research Centre and the biotechnology company Spark Therapeutics, conducted a two-step study to test the efficacy of the IdeS enzyme in animal models. This enzyme naturally reduces the action of IgG immunoglobulins to neutralize the immune response. They first injected subjects immunised against AAVs with IdeS before injecting the gene therapy vector with the same serotype and observed that IdeS neutralized the action of the antibodies. This first step demonstrated the efficacy of the approach.
Then, the teams tested this approach with a view to the possible reinjection of gene therapy treatments. After administering a first dose of AAV vector, then a second dose preceded by an injection of Ides, the researchers found that IdeS allowed the re-administration of the vector by reducing the level of circulating antibodies.
These two studies demonstrate that treatment with IdeS allows repeated administration of AAV gene therapy. This is a significant and promising step forward in the treatment of rare genetic diseases.
“These studies should enable us to test this innovative approach in humans and thus, in the long term, to give AAV-positive patients the possibility of benefiting from gene therapy, despite the presence of antibodies. This could also make it possible to treat patients as soon as the first symptoms of the disease appear (affecting the liver, for example) and, if necessary, to re-administer the gene therapy treatment in an effective manner,” stresses Christian Leborgne, research engineer at Genethon.
“This study represents an important step towards solving a complex and fundamental problem, namely the repeated administration of gene therapy treatments to patients who may need them, and also the treatment of patients who today are not eligible for gene therapy due to the existence of neutralizing antibodies in their systems. This study highlights, once again, the expertise of our researchers who are imagining and developing new approaches to make gene therapy even more effective and increase the number of patients able to access it,” says Frédéric Revah, Chief Executive Officer of Genethon.