Spark touts animal data for a solution to AAV gene therapy's antibody problem
Among all the limitations of using an adeno-associated virus as a vector to deliver a gene — still the most established modality in gene therapy given years of trial and error and finally success — the presence of neutralizing antibodies, whether pre-existing or induced, looms large.
“When I think about the immune responses in AAV, I try to sort of layer them,” Federico Mingozzi, the CSO at Spark Therapeutics, told Endpoints News. “The antibody is the first layer. It’s the first block that you find when you’re trying to do gene transfer.”
Pre-existing antibodies acquired from infections by wild-type AAV disqualify anywhere from 30% to 70% of patients from clinical trials; high titers of antibodies triggered by a first administration of a gene therapy render redosing essentially impossible. But Mingozzi and his team — now working as a subsidiary of Roche — said they have found a technology that can dismantle this layer.
They didn’t invent IdeS, short for immunoglobulin G-degrading enzyme of Streptococcus pyogenes. In fact, the researchers said the “excellent” safety profile the enzyme has accrued in clinical trials for IgG-mediated autoimmune diseases and in transplant patients boosted their confidence in carrying out the new work. Previous studies also suggest that IdeS cleaves antibodies in the bloodstream, but only transiently — which Mingozzi said is perfect for gene therapy.
“Basically all you need is a window of time that allows you to inject the vector and allow the vector to get to the target tissue, and then the vector once it’s inside the cell is protected from antibodies, so you don’t care any longer,” he said. “And this window of time is only a couple of hours.”
Reporting in Nature Medicine, the team wrote that IdeS treatment decreased the levels of IgG in both mice, non-human primates that were then given an AAV8 vector carrying a gene for factor IX. Transgene expression and liver gene transduction also appeared to be higher. The same effects were observed in experiments with human plasma samples, including some from prospective clinical trial participants, they added.
The finding that IdeS worked not just against antibodies that were already there but also new ones developed as a result of vector administration is surprising, Mingozzi said, as the latter often stirs up high and long-lasting titers.
Redosing of gene therapy has been on the wish list of scientists who are concerned about the effects waning over time, an issue that could be especially pertinent for patients receiving an injection as infants.
Other immunity-related issues, of course, may still crop up, such as T cell responses that are currently being controlled by corticosteroids. But Mingozzi is hopeful that the technology will go a long way in extending the reach of these potentially curative treatments, with the most immediate application in liver gene transfer.
While other companies are developing IdeS for other conditions, Spark has filed for IP around this particular use, he said. Preclinical work, including GLP toxicology studies, is ongoing to push it toward the clinic — at which point the development team will have to figure out with regulators how they can redesign and assess trials that will include anti-AAV antibody seropositive patients.