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

doi:10.1016/j.omtm.2023.06.001

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

Mol Ther Methods Clin Dev. 2023 Jun 19:30:303-314. doi: 10.1016/j.omtm.2023.06.001. eCollection 2023 Sep 14.

Authors

Manuela Corti¹, Barry J Byrne¹, Dominic J Gessler^{2

3}, Grace Thompson⁴, Samantha Norman¹, Jenna Lammers¹, Kirsten E Coleman¹, Cristina Liberati¹, Melissa E Elder^{1

5}, Maria L Escolar⁶, Ibrahim S Tuna⁷, Clementina Mesaros^{8

9}, Gary I Kleiner¹⁰, Deborah S Barbouth¹¹, Heather L Gray-Edwards^{2

12}, Nathalie Clement¹, Brian D Cleaver¹, Guangping Gao^{2

13

14}

Affiliations

¹ Powell Gene Therapy Center, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL, USA.
² Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
³ Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, USA.
⁴ Department of Pediatric Surgery, College of Medicine, University of Florida, Gainesville, FL, USA.
⁵ University of Florida Health Shands Children's Hospital, Gainesville, FL, USA.
⁶ Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁷ Department of Radiology, College of Medicine, University of Florida, Gainesville, FL, USA.
⁸ Penn Medicine/Children's Hospital of Philadelphia Center of Excellence in Friedreich's Ataxia, University of Pennsylvania, Philadelphia, PA, USA.
⁹ Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, FL, USA.
¹¹ Division of Clinical and Translational Genetics, Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, FL, USA.
¹² Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA.
¹³ Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA.
¹⁴ Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.

Abstract

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.

Keywords: AAV; Canavan disease; dual route of administration; immune modulation.

Grants and funding

P30 ES013508/ES/NIEHS NIH HHS/United States