"One of the main challenges associated with AAV-mediated gene therapy is neutralizing antibodies that can impact the ability to administer gene therapy," said Federico Mingozzi, Ph.D., chief scientific officer at Spark Therapeutics. "The IdeS technology has the potential to eliminate anti-AAV antibodies that allow for the extended use of gene therapy in a larger segment of candidates who may have been excluded due to pre-existing or developing neutralizing antibodies and also enable vector re-administration."
The study was conducted by an international collaboration of researchers from Spark Therapeutics in the U.S., and Genethon, the Centre de Recherche des Cordeliers (Inserm, Sorbonne Université, Université de Paris) and the National Centre for Scientific Research (CNRS) in France.
AAV-mediated gene therapy allows for the treatment of a growing number of diseases in patients today, however the presence of neutralizing anti-AAV antibodies can lead to limitations of this technology. Specifically, neutralizing anti-AAV IgG pre-exist in up to seventy percent of the population and block the entry of viral vector particles in a given target tissue. Furthermore, high-titer anti-AAV antibody levels usually develop following vector administration and persist long-term thereafter, preventing vector re-administration. To date, researchers have been limited in their ability to bypass the neutralizing activity of anti-AAV IgG.
The study demonstrated that treatment with the IgG-degrading enzyme IdeS, an endopeptidase from Streptococcus pyogenes that specifically hydrolyses human IgG, resulted in a rapid and transient elimination of neutralizing anti-AAV IgG and restored gene therapy efficacy. IdeS is an endopeptidase able to degrade circulating IgG that is currently being tested in transplant patients.
Researchers demonstrated efficacy in vivo using animal models of liver gene transfer, including hemophilia A and B. Hemophilia is a rare genetic bleeding disorder that causes a delay in clot formation as a result of a deficiency in coagulation factor VIII or IX for hemophilia A or B, respectively. In both mice and non-human primates with neutralizing anti-AAV IgG, IdeS treatment prior to the injection of AAV vectors eliminated neutralizing IgG and rescued the expression of the factor VIII or IX in hepatocytes.
Furthermore, administration of AAV vectors systematically induces a neutralizing anti-AAV immune response, making gene therapy inefficient upon subsequent injections of AAV vectors. The study also demonstrated that treatment with IdeS restores the efficacy of the re-administration of AAV vectors, allowing for efficient transgene expression in non-human primates. The research shows that IdeS allows the repeated administration of AAV vectors by blocking the neutralizing activity of anti-AAV IgG in small and large animal models.
Additional studies in the field of gene therapy have the potential to translate these findings to human trials, with the goal of opening a therapeutic window for patients with neutralizing anti-AAV antibodies. Spark will assess and investigate the potential impact of the IdeS technology on its current gene therapy programs and potential applications in the future.
About Spark Therapeutics
At Spark Therapeutics, a fully integrated, commercial company committed to discovering, developing and delivering gene therapies, we challenge the inevitability of genetic diseases, including blindness, hemophilia, lysosomal storage disorders and neurodegenerative diseases. We currently have four programs in clinical trials. At Spark, a member of the Roche Group, we see the path to a world where no life is limited by genetic disease. For more information, visit www.sparktx.com, and follow us on Twitter and LinkedIn.
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