Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys
Article first published online: 27 DEC 2006
Copyright © 2006 American Neurological Association
Annals of Neurology
Volume 60, Issue 6, pages 706–715, December 2006
How to Cite
Kordower, J. H., Herzog, C. D., Dass, B., Bakay, R. A. E., Stansell, J., Gasmi, M. and Bartus, R. T. (2006), Delivery of neurturin by AAV2 (CERE-120)-mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP-treated monkeys. Ann Neurol., 60: 706–715. doi: 10.1002/ana.21032
- Issue published online: 27 DEC 2006
- Article first published online: 27 DEC 2006
- Manuscript Accepted: 29 SEP 2006
- Manuscript Revised: 14 SEP 2006
- Manuscript Received: 21 JUL 2006
We tested the hypothesis that gene delivery of the trophic factor neurturin could preserve motor function and protect nigrostriatal circuitry in hemiparkinsonian monkeys.
An adeno-associated virus–based vector encoding human neurturin (AAV2-NTN; also called CERE-120) was injected into the striatum and substantia nigra of monkeys 4 days after a unilateral intracarotid injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rendered them hemiparkinsonian. Control hemiparkinsonian monkeys received either AAV2 encoding green fluorescent protein or formulation buffer.
Although stable deficits were seen in all control monkeys, AAV2-NTN significantly improved MPTP-induced motor impairments by 80 to 90% starting at approximately month 4 and lasting until the end of the experiment (month 10). AAV2-NTN significantly preserved nigral neurons, significantly preserved striatal dopaminergic innervation, and activated phospho-extracellular signal–regulated kinase, consistent with a mechanism involving a trophic factor–initiated molecular cascade. Histological analyses of numerous brain regions, including the cerebellum, showed normal cytoarchitecture and no aberrant pathology.
These data demonstrate that AAV2-NTN (CERE-120) can preserve function and anatomy in degenerating nigrostriatal neurons and are supportive of ongoing clinical tests in Parkinson's disease patients. Ann Neurol 2006;60:706–715