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Start Over Author "Honnet G" Journal human gene therapy
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1. Prevalence and Relevance of Pre-Existing Anti-Adeno-Associated Virus Immunity in the Context of Gene Therapy for Crigler-Najjar Syndrome

Author

Sem J. Aronson, Angelo Di Giorgio, Ulrich Baumann, Virginie Delahais, Lorenzo D'Antiga, Fanny Collaud, Aurélie Hubert, Géraldine Honnet, Federico Mingozzi, Nicola Brunetti-Pierri, Philippe Labrune, Norman Junge, Robert J. de Knegt, Ulrich Beuers, Virginia Maria Ginocchio, Piter J. Bosma, Philippe Veron, Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon, AP-HP - Hôpital Antoine Béclère [Clamart], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Gastroenterology and Hepatology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Università degli studi di Napoli Federico II, University of Amsterdam [Amsterdam] (UvA), Graduate School, Tytgat Institute for Liver and Intestinal Research, AGEM - Digestive immunity, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, École Pratique des Hautes Études (EPHE), University of Naples Federico II = Università degli studi di Napoli Federico II, Gastroenterology & Hepatology, Aronson, S. J., Veron, P., Collaud, F., Hubert, A., Delahais, V., Honnet, G., De Knegt, R. J., Junge, N., Baumann, U., Di Giorgio, A., D'Antiga, L., Ginocchio, virginia maria, Brunetti-Pierri, N., Labrune, P., Beuers, U., Bosma, P. J., Mingozzi, F., Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM), and COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)

Subjects
Serotype, Male, anti-AAV neutralizing antibodie, Crigler–Najjar syndrome, [SDV]Life Sciences [q-bio], Genetic enhancement, anti-AAV neutralizing antibodies, Gene Expression, medicine.disease_cause, Antibodies, Viral, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Mice, 0302 clinical medicine, Glucuronosyltransferase, Child, Adeno-associated virus, Research Articles, Crigler-Najjar Syndrome, 0303 health sciences, biology, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Dependovirus, 3. Good health, Titer, unconjugated hyperbilirubinemia, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Liver, 030220 oncology & carcinogenesis, Child, Preschool, Phenobarbital, Molecular Medicine, Female, Antibody, AAV gene therapy, Plasmids, Adult, Adolescent, pre-existing immunity, Transfection, Virus, 03 medical and health sciences, Capsid, Immunity, Genetics, medicine, Animals, Humans, Molecular Biology, 030304 developmental biology, business.industry, Immunization, Passive, Bilirubin, Genetic Therapy, Phototherapy, medicine.disease, Antibodies, Neutralizing, Immunity, Innate, Mice, Inbred C57BL, HEK293 Cells, Immunology, biology.protein, UGT1A1, business, Excitatory Amino Acid Antagonists
Abstract

International audience; Adeno-associated virus (AAV) vector-mediated gene therapy is currently evaluated as a potential treatment for Crigler-Najjar syndrome (CN) (NCT03466463). Pre-existing immunity to AAV is known to hinder gene transfer efficacy, restricting enrollment of seropositive subjects in ongoing clinical trials. We assessed the prevalence of anti-AAV serotype 8 (AAV8) neutralizing antibodies (NAbs) in subjects affected by CN and investigated the impact of low NAb titers (

Published
2019
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2. Prevalence and Relevance of Pre-Existing Anti-Adeno-Associated Virus Immunity in the Context of Gene Therapy for Crigler-Najjar Syndrome.

Author

Aronson SJ, Veron P, Collaud F, Hubert A, Delahais V, Honnet G, de Knegt RJ, Junge N, Baumann U, Di Giorgio A, D'Antiga L, Ginocchio VM, Brunetti-Pierri N, Labrune P, Beuers U, Bosma PJ, and Mingozzi F

Subjects
Adolescent, Adult, Animals, Bilirubin immunology, Bilirubin metabolism, Capsid immunology, Capsid metabolism, Child, Child, Preschool, Crigler-Najjar Syndrome genetics, Crigler-Najjar Syndrome immunology, Crigler-Najjar Syndrome pathology, Dependovirus immunology, Excitatory Amino Acid Antagonists therapeutic use, Female, Gene Expression, Glucuronosyltransferase deficiency, Glucuronosyltransferase immunology, HEK293 Cells, Humans, Immunity, Innate, Immunization, Passive, Liver immunology, Liver pathology, Male, Mice, Mice, Inbred C57BL, Phenobarbital therapeutic use, Phototherapy methods, Plasmids chemistry, Plasmids metabolism, Transfection, Antibodies, Neutralizing biosynthesis, Antibodies, Viral biosynthesis, Crigler-Najjar Syndrome therapy, Dependovirus genetics, Genetic Therapy methods, Glucuronosyltransferase genetics
Abstract

Adeno-associated virus (AAV) vector-mediated gene therapy is currently evaluated as a potential treatment for Crigler-Najjar syndrome (CN) (NCT03466463). Pre-existing immunity to AAV is known to hinder gene transfer efficacy, restricting enrollment of seropositive subjects in ongoing clinical trials. We assessed the prevalence of anti-AAV serotype 8 (AAV8) neutralizing antibodies (NAbs) in subjects affected by CN and investigated the impact of low NAb titers (<1:5) on liver gene transfer efficacy in an in vivo passive immunization model. A total of 49 subjects with a confirmed molecular diagnosis of CN were included in an international multicenter study (NCT02302690). Pre-existing NAbs against AAV8 were detected in 30.6% (15/49) of screened patients and, in the majority of positive cases, cross-reactivity to AAV2 and AAV5 was detected. To investigate the impact of low NAbs on AAV vector-mediated liver transduction efficiency, adult wild-type C57BL/6 mice were passively immunized with pooled human donor-derived immunoglobulins to achieve titers of up to 1:3.16. After immunization, animals were injected with different AAV8 vector preparations. Hepatic vector gene copy number was unaffected by low anti-AAV8 NAb titers when column-purified AAV vector batches containing both full and empty capsids were used. In summary, although pre-existing anti-AAV8 immunity can be found in about a third of subjects affected by CN, low anti-AAV8 NAb titers are less likely to affect liver transduction efficiency when using AAV vector preparations manufactured to contain both full and empty capsids. These findings have implications for the design of liver gene transfer clinical trials and for the definition of inclusion criteria related to seropositivity of potential participants.

Published
2019
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