Spark Study Shows Path to Enable Gene Therapy in the Presence of Neutralizing Anti-AAV Antibodies

Rare Daily Staff

One of the greatest challenges with gene therapies is the uncertainty surrounding its durability and the inability to re-dose patients due to the development of neutralizing antibodies to the delivery vector.

Now gene therapy biotech developer Spark Therapeutics has published new research in the journal Nature Medicine demonstrating that treatment with immunoglobulin G-degrading (IgG) enzyme of Streptococcus pyogenes (IdeS) resulted in rapid and transient reduction of neutralizing anti-adeno-associated virus (AAV) antibodies and restored gene therapy efficacy in controlled laboratory tests of animal models.

“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, 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 United States 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 patients who have had transplants.

Researchers showed 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.

Administration of AAV vectors also systematically induces a neutralizing anti-AAV immune response, making gene therapy inefficient upon subsequent injections of AAV vectors. The study showed 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.

Spark says it plans additional gene therapy studies to potentially translate its findings to human trials, with the goal of opening a therapeutic window for patients with neutralizing anti-AAV antibodies. Spark plans to assess and investigate the potential impact of the IdeS technology on its current gene therapy programs and potential applications in the future.