While there are several viruses that can carry genetic cargo to cells, the gene therapy delivery workhorse has been adeno-associated viruses (AAVs). AAVs are not without their limits, despite their promise to amplify the present renaissance of gene therapy, and their function in two FDA-approved gene therapy products. Not only do they have a small cargo holding capacity, but since AAVs are natural viruses, many individuals have troublesome antibodies to them.
A research team has now succeeded in inhibiting the immune response caused by the presence of AAV antibodies as a result of natural immunity or after gene therapy. This outcome opens up new treatment prospects and opens up the possibility of more patients being treated.
The study wa publish in Nature under title “IgG-cleaving endopeptidase enables in vivo gene therapy in the presence of anti-AAV neutralizing antibodies,”
Frédéric Revah, PhD, CEO of Genethon, says: "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, as well as the treatment of patients who are not eligible for gene therapy today because of the existence of neutralising antibodies in their systems."
In many cases, once it comes into contact with this virus, the body develops neutralizing antibodies. About 30 percent and 50 percent of humans are naturally immunised for medicinal purposes against most AAVs used. As a result, AAV gene therapy is actually unable to support a significant number of patients. In addition, the first injection of an AAV results in an immune reaction to the vector, and any subsequent AAV gene therapy is precluded.
Immunosuppression is often involved in techniques aimed at overcoming anti-AAV antibodies, and they are not successful in eliminating pre-existing antibodies. An enzyme that is capable of degrading circulating IgG is imlifidase (IdeS). IdeS is currently being studied in transplant patients and the authors noted that, in the sense of gene therapy, they sought to decide whether IdeS could suppress anti-AAV antibodies. To assess the efficacy of IdeS, the researchers used animal models.
Effective cleavage of pooled human IgG in vitro upon enzyme treatment was shown in the results. The authors wrote that "IdeS administration decreased anti-AAV antibodies and allowed efficient liver gene transfer" in mice passively immunised with intravenous Ig.
The method was then scaled up to nonhuman primates, a natural host for wild-type AAV. Before injecting the gene therapy vector of the same serotype, researchers injected the IdeS enzyme into subjects with anti-AAV IgG neutralisation and then found that the IdeS treatment neutralised the antibody action. For subjects with natural immunity, this first step presented evidence of the feasibility of this strategy.
With a view to the potential reinjection of gene therapy drugs, the teams then checked this strategy. Therefore, the first dose of the AAV vector was administered, then the second dose after the injection of IdeS. They observed that IdeS allowed the re-administration of the vector by reducing the amount of circulating antibodies.
Finally, IdeS decreased levels of anti-AAV antibodies from in vitro human plasma samples, including plasma from participants in prospective gene therapy trials.
Studies have shown that treatment with IdeS allows AAV gene therapy to be repeatedly administered. This is an important and exciting step forward in the treatment of rare genetic diseases because, if the success of this technique is verified in humans, it will allow the first symptoms of the disease to be treated by patients and, if appropriate, to re-inject a gene therapy product.
The outcomes include a possible strategy for resolving pre-existing AAV-based gene therapy antibodies.
"These studies should allow us to test this innovative approach in humans and thus, in the long term, give AAV-positive patients, despite the presence of antibodies, the opportunity to benefit from gene therapy," said Christian Leborgne, Genethon's research engineer. "This could also make it possible to treat patients as soon as the first symptoms of the disease appear (for example, affecting the liver) and, if necessary, to effectively re-administer gene therapy therapy."
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