Anti-hIgE gene therapy of peanut-induced anaphylaxis in a humanized murine model of peanut allergy - 18/04/17
Abstract |
Background |
Peanuts are the most common food to provoke fatal or near-fatal anaphylactic reactions. Treatment with an anti-hIgE mAb is efficacious but requires frequent parenteral administration.
Objective |
Based on the knowledge that peanut allergy is mediated by peanut-specific IgE, we hypothesized that a single administration of an adeno-associated virus (AAV) gene transfer vector encoding for anti-hIgE would protect against repeated peanut exposure in the host with peanut allergy.
Methods |
We developed a novel humanized murine model of peanut allergy that recapitulates the human anaphylactic response to peanuts in NOD-scid IL2Rgammanull mice transferred with blood mononuclear cells from donors with peanut allergy and then sensitized with peanut extract. As therapy, we constructed an adeno-associated rh.10 serotype vector coding for a full-length, high-affinity, anti-hIgE antibody derived from the Fab fragment of the anti-hIgE mAb omalizumab (AAVrh.10anti-hIgE). In the reconstituted mice peanut-specific IgE was induced by peanut sensitization and hypersensitivity, and reactions were provoked by feeding peanuts to mice with symptoms similar to those of human subjects with peanut allergy.
Results |
A single administration of AAVrh.10anti-hIgE vector expressed persistent levels of anti-hIgE. The anti-hIgE vector, administered either before sensitization or after peanut sensitization and manifestation of the peanut-induced phenotype, blocked IgE-mediated alterations in peanut-induced histamine release, anaphylaxis scores, locomotor activity, and free IgE levels and protected animals from death caused by anaphylaxis.
Conclusion |
If this degree of persistent efficacy translates to human subjects, AAVrh.10anti-hIgE could be an effective 1-time preventative therapy for peanut allergy and possibly other severe, IgE-mediated allergies.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Peanut allergy, food allergy, omalizumab, IgE, gene therapy, mouse model
Abbreviations used : AAV, GVHD, hIgE, NSG, PCA
Plan
| Supported by the Parker B. Francis Fellowship Program and the Department of Genetic Medicine, Weill Cornell Medical College. |
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| Disclosure of potential conflict of interest: O. E. Pagovich is a listed investor on a patent application subsequent to the completion of this work. M. J. Chiuchiolo is a listed investor on a patent application subsequent to the completion of this work. R. G. Crystal serves as a consultant and holds stock options for Adverum Biotechnologies and is a listed investor on a patent application subsequent to the completion of this work. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 138 - N° 6
P. 1652 - décembre 2016 Retour au numéro
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