Nat Med: Research to suppress AAV-related immune responses will drive rapid progress in gene therapy!

JUNE 14, 2020 /PRNewswire/ -- A team of researchers from Genethon, along with a team of researchers from CNRS/Inserm and Spark Therapeutics, recently announced in the journal Nature Medicine that they have successfully suppressed the immune response caused by AAV antibodies caused by natural immunity or gene therapy, thanks to the IdeS enzymeThis result opens up new therapeutic prospects and the possibility of treating more patientsGene therapy involves injecting therapeutic genes into organisms using vectors, a "transport vehicle" that crosses all biological barriers within the cell into the nucleusThe most commonly used vectors come from viruses, such as adenoviruses (AAVs), especially for gene therapy for muscles, livers, eyes, etcIn many cases, once exposed to the virus, the body produces neutralized immunoglobulins (IgGs), specific antibodies that inhibit AAVsIt is believed that 30 to 50 per cent of people have natural immunity to most AAVs for therapeutic purposesAs a result, a large number of patients are currently unable to benefit from AAV gene therapyIn addition, the first injection of AAV results in an immune response to the vector, thus excluding any subsequent AAV gene therapyPhoto Source: Overcoming this barrier is an important factor in maximizing patient careTo eliminate immune responses induced by immunoglobulin IgG, Genethon researcher Giuseppe Ronzitti, CNRS/Inserm's S?bastien Lacroix-Desmazes and Spark STherapeutics Federico Mingozzi used animal models to test the efficacy of IdeSase, a peptide-inline enzyme that naturally reduces the action of antibodiesThe study was conducted in two steps: before injecting the same serotype of gene therapy vector, the researchers injected the IdeS enzyme into the subjects and neutralized the anti-AAV IgG, and then observed the effects of the ideS treatment and antibodiesThis first step demonstrates the effectiveness of this method for subjects with natural immunityThe team then tested the method with a view to potentially re-injecting gene therapy drugsSo they gave the first dose of AAV vector and then the second dose of AAV carrier after injecting ideS enzymeThey observed that by lowering the level of circulating antibodies, ideS enzymes allowed re-administrationBoth experiments show that IdeS enzyme therapy allows for repeated use of AAV gene therapy This is an important and promising step in the treatment of rare genetic diseases, because if the efficacy of the technique is proven in humans, it will likely lead to treatment in patients with the initial symptoms of the disease and, if necessary, re-injection of gene therapy products "These studies should allow us to test this innovative approach in humans, so in the long run, it could benefit AAV-positive patients from gene therapy." This may also allow patients to be treated with the first symptoms of the disease once they develop, and, if necessary, can be re-treated in an effective manner," said Christian Leborgne, Genethon research engineer (BioValleyBioon.com) References: Christian Leborgne et al IgG-cleaving endopeptidase yn vivo gene therapy in the presence of anti-AAV neutral anti-anti-anti-antibodies, Nature Medicine (2020) DOI: 10.1038/s41591-020-0911-7