Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease - PubMed (original) (raw)
Clinical Trial
doi: 10.1002/1531-8249(200007)48:1<27::aid-ana6>3.0.co;2-6.
C G Janson, L Bilaniuk, Z Wang, F Sorgi, L Huang, R Matalon, R Kaul, Z Zeng, A Freese, S W McPhee, E Mee, M J During
Affiliations
- PMID: 10894213
- DOI: 10.1002/1531-8249(200007)48:1<27::aid-ana6>3.0.co;2-6
Clinical Trial
Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease
P Leone et al. Ann Neurol. 2000 Jul.
Erratum in
- Ann Neurol 2000 Sep;48(3):398. Bilianuk L [corrected to Bilaniuk L]
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 (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.
Comment in
- Gene therapy for Canavan disease?
Fink DJ. Fink DJ. Ann Neurol. 2000 Jul;48(1):9-10. Ann Neurol. 2000. PMID: 10894210 Review. No abstract available.
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