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1. Cell-mediated immunity to NAGLU transgene following intracerebral gene therapy in children with Mucopolysaccharidosis type IIIB syndrome

Author

Gougeon, Marie-Lise, Poirier-Beaudouin, Béatrice, Ausseil, Jérome, Zérah, Michel, Artaud, Cécile, Heard, Jean-Michel, Deiva, Kumaran, Tardieu, Marc, Département Infection et Epidémiologie - Department of Infection and Epidemiology, Institut Pasteur [Paris], Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de neurochirurgie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Biothérapies pour les Maladies Neurodégénératives, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Service de Neurologie Pédiatrique [CHU Bicêtre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Institut Pasteur sponsored the study during thefirst 30 monthsand UniQure sponsored it for the following 36 months. Thestudy was supported by funds from the'Association FrançaiseContre les Myopathies (AFM)', the patients‘association'Vaincreles Maladies Lysosomales', the Institut Pasteur, the Conny MaevaCharitable Foundation, and a gift from the Akbaraly family., Institut Pasteur [Paris] (IP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Center for Immunology of Viral Infections and Autoimmune Diseases, Le Kremlin Bicêtre, and Institut Pasteur sponsored the study during thefirst 30 monthsand UniQure sponsored it for the following 36 months. Thestudy was supported by funds from the'Association Française Contre les Myopathies (AFM)', the patients‘association'Vaincreles Maladies Lysosomales', the Institut Pasteur, the Conny MaevaCharitable Foundation, and a gift from the Akbaraly family.

Subjects
NAGLU, T-Lymphocytes, [SDV]Life Sciences [q-bio], Genetic Vectors, Immunology, MESH: Mucopolysaccharidosis III / complications, T cells, cellular immunity, Lymphocyte Activation, MESH: Immunity, Cellular, MESH: Acetylglucosaminidase / genetics, MESH: Genetic Therapy / adverse effects, Mucopolysaccharidosis III, MESH: Mucopolysaccharidosis III / genetics, MESH: Child, Acetylglucosaminidase, MESH: Acetylglucosaminidase / immunology, Humans, Transgenes, MESH: Lymphocyte Activation, Child, Original Research, Immunity, Cellular, Drug Administration Routes, MESH: Cytokines / metabolism, MESH: Genetic Therapy / methods, MESH: Genetic Vectors / administration & dosage, AAV, Genetic Therapy, RC581-607, cytokines, MESH: Drug Administration Routes, MESH: Genetic Vectors / genetics, MESH: Immunologic Memory, MPS IIIB, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunologic diseases. Allergy, CNS, Immunologic Memory
Abstract

International audience; Mucopolysaccharidosis type IIIB syndrome (Sanfilippo disease) is a rare autosomic recessif disorder caused by mutations in the α-N-acetylglucosaminidase (NAGLU) gene coding for a lysosomal enzyme, leading to neurodegeneration and progressive deterioration of cognitive abilities in affected children. To supply the missing enzyme, several recent human gene therapy trials relied on the deposit of adeno-associated virus (AAV) vectors directly into the brain. We reported safety and efficacy of an intracerebral therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov/ct2/show/NCT03300453), with a recombinant AAV serotype 2/5 (rAAV2/5) coding human NAGLU in four children with MPS IIIB syndrome receiving immunosuppression. It was reported that AAV-mediated gene therapies might elicit a strong host immune response resulting in decreased transgene expression. To address this issue, we performed a comprehensive analysis of cellular immunity and cytokine patterns generated against the therapeutic enzyme in the four treated children over 5.5 years of follow-up. We report the emergence of memory and polyfunctional CD4+ and CD8+ T lymphocytes sensitized to the transgene soon after the start of therapy, and appearing in peripheral blood in waves throughout the follow-up. However, this response had no apparent impact on CNS transgene expression, which remained stable 66 months after surgery, possibly a consequence of the long-term immunosuppressive treatment. We also report that gene therapy did not trigger neuroinflammation, evaluated through the expression of cytokines and chemokines in patients' CSF. Milder disease progression in the youngest patient was found associated with low level and less differentiated circulating NAGLU-specific T cells, together with the lack of proinflammatory cytokines in the CSF. Findings in this study support a systematic and comprehensive immunomonitoring approach for understanding the impact immune reactions might have on treatment safety and efficacy of gene therapies.

Published
2021
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2. Intracerebral Gene Therapy in Four Children with Sanfilippo B Syndrome: 5.5-Year Follow-Up Results

Author

Jérôme Ausseil, Béatrice Poirier-Beaudouin, Marie-Lise Gougeon, Béatrice Husson, Dimitrios I. Zafeiriou, Marc Tardieu, Giancarlo Parenti, Kumaran Deiva, Michel Zerah, Stéphanie de Bournonville, Jean-Michel Heard, Deiva, K., Ausseil, J., De Bournonville, S., Zerah, M., Husson, B., Gougeon, M. -L., Poirier-Beaudouin, B., Zafeiriou, D., Parenti, G., Heard, J. -M., Tardieu, M., Université Paris-Saclay, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Département de Santé Globale - Department Global Health, Institut Pasteur [Paris] (IP), Aristotle University of Thessaloniki, University of Naples Federico II = Università degli studi di Napoli Federico II, Telethon Institute of Genetics and Medicine = Istituto Telethon di Genetica e Medicina (TIGEM), Biothérapies pour les Maladies Neurodégénératives, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and This study was supported by uniQure, Association Française contre les Myopathies, Institut Pasteur, and Vaincre les Maladies Lysosomales. The study was sponsored by Institut Pasteur during the first 30 months and by uniQure during the following 36 months.

Subjects
cognition, safety, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Genetic enhancement, medicine.medical_treatment, T-Lymphocytes, security, intra cerebral gene therapy, Follow-Up Studie, Mucopolysaccharidosis III, Cerebrospinal fluid, Atrophy, Internal medicine, Genetics, medicine, Clinical endpoint, Humans, Adverse effect, Molecular Biology, MESH: Genetic Therapy, MESH: Humans, business.industry, MESH: Child, Preschool, MESH: Infant, Newborn, Infant, Newborn, Infant, Brain, MESH: Mucopolysaccharidosis III* / genetics, Immunosuppression, MESH: Follow-Up Studies, Genetic Therapy, medicine.disease, MESH: Infant, MESH: Mucopolysaccharidosis III* / therapy, Clinical trial, MESH: T-Lymphocytes, T-Lymphocyte, Child, Preschool, outcome, [SDV.IMM]Life Sciences [q-bio]/Immunology, Molecular Medicine, MESH: Brain / diagnostic imaging, business, Neurocognitive, Follow-Up Studies, Human
Abstract

International audience; We report the safety (primary endpoint) and efficacy (secondary endpoint) of a novel intracerebral gene therapy at 5.5 years of follow-up in children with Sanfilippo B. An uncontrolled, phase 1/2 clinical trial was performed in four patients aged 20, 26, 30, and 53 months. Treatment consisted of 16 intracerebral and cerebellar deposits of a recombinant adeno-associated viral vector encoding human α-N-acetylglucosaminidase (rAAV2/5-hNAGLU) plus immunosuppression. An intermediate report at 30 months was previously published. Thirty treatment-emergent adverse events were reported between 30 and 66 months after surgery, including three classified as severe with no serious drug reactions. At 5.5 years, NAGLU activity was persistently detected in the lumbar cerebrospinal fluid (18% of unaffected control level). Circulating T cells reacting against NAGLU peptides were present, indicating a lack of acquired tolerance. Patients 2, 3, and 4 showed progressive brain atrophy and neurocognitive evolution that did not differ from untreated Sanfilippo A/B children. Patient 1, enrolled at 20 months of age, had a milder disease with normal brain imaging and a significantly better cognitive outcome than the three other patients and untreated patients, although not equivalent to normal children. After 5.5 years, the primary endpoint of this study was achieved with a good safety profile of the proposed treatment. We have also observed sustained enzyme production in the brain and absence of immunological tolerance. Cognitive benefit was not confirmed in the three oldest patients. Milder disease in the youngest patient supports further investigations of adeno-associated vector-mediated intracerebral gene therapy in Sanfilippo B.

Published
2021
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