Intracerebral Gene Therapy in Four Children with Sanfilippo B Syndrome: 5.5-Year Follow-Up Results
| Autor: | 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 |
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| Přispěvatelé: | 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), 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. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | Human Gene Therapy Human Gene Therapy, 2021, 32 (19-20), pp.1251-1259. ⟨10.1089/hum.2021.135⟩ |
| ISSN: | 1043-0342 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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