Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease

P. Leone, C. G. Janson, L. Bilianuk, Z. Wang, F. Sorgi, L. Huang, Reuben Matalon, R. Kaul, Z. Zeng, A. Freese, S. W. McPhee, E. Mee, M. J. During

Research output: Contribution to journalArticle

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Abstract

With the ultimate goal of developing safe and effective in vivo gene therapy for the treatment of Canavan disease and other neurological disorders, we developed a non-viral lipid-entrapped, polycation-condensed delivery system (LPD) for central nervous system gene transfer, in conjunction with adeno-associated virus (AAV)-based plasmids containing recombinant aspartoacylase (ASIA). The gene delivery system was tested in healthy rodents and primates, before proceeding to preliminary studies in 2 children with Canavan disease. Toxicity and expression testing was first carried out in human 293 cells, which demonstrated effective transduction of cells and high levels of functional ASPA activity. We performed in vivo toxicity and expression testing of LPD/pAAVaspa and LPD/pAAVlac in rodents, which demonstrated widespread gene expression for more than 10 months after intraventricular delivery, and local expression in deep brain nuclei and white matter tracts for more than 6 months after intraparenchymal injections, with no significant adverse effects. We also performed intraventricular delivery of LPD/pAAVaspa to 2 cynomologous monkeys, with 2 additional monkeys receiving LPD and saline controls. None of the monkeys demonstrated significant adverse effects, and at 1 month the 2 LPD/pAAVaspa monkeys were positive for human ASPA transcript by reverse transcriptase polymerase chain reaction of brain tissue punches. Finally, we performed the first in vivo gene transfer study for a human neurodegenerative disease in 2 children with Canavan disease to assess the in vivo toxicity and efficacy of ASPA gene delivery. Our results suggest that LPD/pAAVaspa is well tolerated in human subjects and is associated with biochemical, radiological, and clinical changes.

Original languageEnglish (US)
Pages (from-to)27-38
Number of pages12
JournalAnnals of Neurology
Volume48
Issue number1
DOIs
StatePublished - 2000

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Canavan Disease
Central Nervous System
Lipids
Haplorhini
Genes
Therapeutics
Rodentia
Gene Transfer Techniques
Dependovirus
Brain
aspartoacylase
polycations
Nervous System Diseases
Reverse Transcriptase Polymerase Chain Reaction
Neurodegenerative Diseases
Genetic Therapy
Primates
Plasmids
Gene Expression
Injections

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. / Leone, P.; Janson, C. G.; Bilianuk, L.; Wang, Z.; Sorgi, F.; Huang, L.; Matalon, Reuben; Kaul, R.; Zeng, Z.; Freese, A.; McPhee, S. W.; Mee, E.; During, M. J.

In: Annals of Neurology, Vol. 48, No. 1, 2000, p. 27-38.

Research output: Contribution to journalArticle

Leone, P, Janson, CG, Bilianuk, L, Wang, Z, Sorgi, F, Huang, L, Matalon, R, Kaul, R, Zeng, Z, Freese, A, McPhee, SW, Mee, E & During, MJ 2000, 'Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease', Annals of Neurology, vol. 48, no. 1, pp. 27-38. https://doi.org/10.1002/1531-8249(200007)48:1<27::AID-ANA6>3.0.CO;2-6
Leone, P. ; Janson, C. G. ; Bilianuk, L. ; Wang, Z. ; Sorgi, F. ; Huang, L. ; Matalon, Reuben ; Kaul, R. ; Zeng, Z. ; Freese, A. ; McPhee, S. W. ; Mee, E. ; During, M. J. / Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. In: Annals of Neurology. 2000 ; Vol. 48, No. 1. pp. 27-38.
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AU - Janson, C. G.

AU - Bilianuk, L.

AU - Wang, Z.

AU - Sorgi, F.

AU - Huang, L.

AU - Matalon, Reuben

AU - Kaul, R.

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AU - Freese, A.

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AU - Mee, E.

AU - During, M. J.

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