Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation

Manuela Corti; Barry J. Byrne; Dominic J. Gessler; Grace Thompson; Samantha Norman; Jenna Lammers; Kirsten E. Coleman; Cristina Liberati; Melissa E. Elder; Maria L. Escolar; Ibrahim S. Tuna; Clementina Mesaros; Gary I. Kleiner; Deborah S. Barbouth; Heather L. Gray-Edwards; Nathalie Clement; Brian D. Cleaver; Guangping Gao

Molecular Therapy: Methods & Clinical Development (Sep 2023)

Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation

Manuela Corti,
Barry J. Byrne,
Dominic J. Gessler,
Grace Thompson,
Samantha Norman,
Jenna Lammers,
Kirsten E. Coleman,
Cristina Liberati,
Melissa E. Elder,
Maria L. Escolar,
Ibrahim S. Tuna,
Clementina Mesaros,
Gary I. Kleiner,
Deborah S. Barbouth,
Heather L. Gray-Edwards,
Nathalie Clement,
Brian D. Cleaver,
Guangping Gao

Affiliations

Manuela Corti: Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA
Barry J. Byrne: Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA; Corresponding author Barry J. Byrne, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA.
Dominic J. Gessler: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, USA
Grace Thompson: Department of Pediatric Surgery, College of Medicine, University of Florida, Gainesville, FL, USA
Samantha Norman: Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA
Jenna Lammers: Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA
Kirsten E. Coleman: Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA
Cristina Liberati: Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA
Melissa E. Elder: Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA; University of Florida Health Shands Children’s Hospital, Gainesville, FL, USA
Maria L. Escolar: Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Ibrahim S. Tuna: Department of Radiology, College of Medicine, University of Florida, Gainesville, FL, USA
Clementina Mesaros: Penn Medicine/Children’s Hospital of Philadelphia Center of Excellence in Friedreich’s Ataxia, University of Pennsylvania, Philadelphia, PA, USA; Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Gary I. Kleiner: Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, FL, USA
Deborah S. Barbouth: Division of Clinical and Translational Genetics, Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA
Heather L. Gray-Edwards: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA
Nathalie Clement: Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA
Brian D. Cleaver: Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA
Guangping Gao: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA

Journal volume & issue: Vol. 30
pp. 303 – 314

Abstract

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Gene replacement therapy is a rational therapeutic strategy and clinical intervention for neurodegenerative disorders like Canavan disease, a leukodystrophy caused by biallelic mutations in the aspartoacylase (ASPA) gene. We aimed to investigate whether simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA provides a safe and effective therapeutic strategy in an open-label, individual-patient, expanded-access trial for Canavan disease. Immunomodulation was given prophylactically prior to adeno-associated virus (AAV) treatment to prevent an immune response to ASPA or the vector capsid. The patient served as his own control, and change from baseline was assessed by clinical pathology tests, vector genomes in the blood, antibodies against ASPA and AAV capsids, levels of cerebrospinal fluid (CSF) N-acetylaspartate (NAA), brain water content and morphology, clinical status, and motor function tests. Two years post treatment, the patient’s white matter myelination had increased, motor function was improved, and he remained free of typical severe epilepsy. NAA level was reduced at 3 months and remained stable up to 4 years post treatment. Immunomodulation prior to AAV exposure enables repeat dosing and has prevented an anti-transgene immune response. Dual-route administration of gene therapy may improve treatment outcomes.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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