Editors' ChoiceGene Therapy

Clearing the path for gene therapy

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Science Translational Medicine  08 Jul 2020:
Vol. 12, Issue 551, eabd3080
DOI: 10.1126/scitranslmed.abd3080


Degrading antibodies allows gene transfer in the presence of anti-AAV antibodies.

Gene therapy is a clinical reality, and product development is progressing at an astonishing speed. According to a Food and Drug Administration commissioner statement, with 10 to 20 new approved products per year, gene and cell therapies may potentially represent up to 40% of all new drug output by 2025. Several candidate patients, however, are deemed ineligible for systemic gene therapy due to the presence of preexisting immunity against widely used adeno-associated virus (AAV) vectors.

Antibodies against AAV are present in the blood of 20 to 80% of individuals, depending on the capsid serotype. Even at low titers, these antibodies inhibit AAV entry into target cells. In a recent study, Leborgne et al. used an innovative method to enzymatically degrade circulating serum antibodies before the application of AAV gene therapy. The study used imlifidase, an immunoglobulin G (IgG)–degrading enzyme derived from bacteria.

The authors set up a gene transfer experiment using factor IX or factor VIII transgenes for hemophilia gene therapy. The antibody degradation strategy was tested in a passively immunized mouse model and in non-human primates, which naturally carry anti-AAV antibodies. One day before the injection of AAV vectors, animals received imlifidase treatment. Treated animals exhibited a decrease of anti-AAV8 neutralizing antibody titers in the serum allowing for enhanced factor IX expression in the liver after AAV gene therapy. Importantly, this treatment was also effective in the even more challenging setting of AAV re-administration. AAV-immunized non-human primates were injected a therapeutic AAV vector encoding for factor VIII, and liver expression was noted in animals receiving imlifidase.

This study suggests imlifidase as a potential strategy to enable systemic gene therapy in the presence of low-to-moderate antibody titers. It is not clear from the current study what the titer cutoff is, above which the therapy is no longer effective. Imlifidase is currently being tested in clinical trials in heparin-induced thrombocytopenia and antibody-mediated graft rejection. It has an excellent safety profile; thus clinical translation for another indication might be more rapid. However, it will be crucial to find a specific gene therapy indication for early clinical trials, and hemophilia gene therapy has not yet received market approval. The future will tell us whether there is a clear path for AAV gene therapy.

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