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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, R. ; Kaul, R. ; Zeng, Z. ; Freese, A. ; McPhee, S. W. ; Mee, E. ; During, M. J.

Annals of neurology, 2000-07, Vol.48 (1), p.27-38 [Periódico revisado por pares]

New York: John Wiley & Sons, Inc

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Título:
Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease
Autor: Leone, P. ; Janson, C. G. ; Bilianuk, L. ; Wang, Z. ; Sorgi, F. ; Huang, L. ; Matalon, R. ; Kaul, R. ; Zeng, Z. ; Freese, A. ; McPhee, S. W. ; Mee, E. ; During, M. J.
Assuntos: Amidohydrolases - genetics ; Amidohydrolases - metabolism ; Animals ; Animals, Newborn ; beta-Galactosidase - genetics ; beta-Galactosidase - metabolism ; Biological and medical sciences ; Brain - pathology ; Brain - physiopathology ; Canavan Disease - enzymology ; Canavan Disease - genetics ; Canavan Disease - therapy ; Cells, Cultured ; Central Nervous System - enzymology ; Central Nervous System - physiopathology ; Child, Preschool ; Errors of metabolism ; Genetic Therapy ; Humans ; Infant ; Lipids (lysosomal enzyme disorders, storage diseases) ; Macaca fascicularis ; Magnetic Resonance Imaging ; Male ; Medical sciences ; Metabolic diseases ; Pilot Projects ; Rats ; Rats, Inbred F344 ; Treatment Outcome
É parte de: Annals of neurology, 2000-07, Vol.48 (1), p.27-38
Notas: New Zealand Health Research Council
ArticleID:ANA6
istex:6C8F894E2ED2F602142E808DAFF71F3FB995E2CD
Canavan Research Fund
ark:/67375/WNG-C72GZJJ7-8
Descrição: 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 (ASPA). 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. Ann Neurol 2000;48:27–38
Editor: New York: John Wiley & Sons, Inc
Idioma: Inglês

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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, R. ; Kaul, R. ; Zeng, Z. ; Freese, A. ; McPhee, S. W. ; Mee, E. ; During, M. J.

New York: John Wiley & Sons, Inc

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