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Delivery of neurturin by AAV2 (CERE‐120)‐mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP‐treated monkeys

Identifieur interne : 001326 ( Main/Exploration ); précédent : 001325; suivant : 001327

Delivery of neurturin by AAV2 (CERE‐120)‐mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP‐treated monkeys

Auteurs : Jeffrey H. Kordower [États-Unis] ; Christopher D. Herzog [États-Unis] ; Biplob Dass [États-Unis] ; Roy A. E. Bakay [États-Unis] ; James Stansell Iii [États-Unis] ; Mehdi Gasmi [États-Unis] ; Raymond T. Bartus [États-Unis]

Source :

RBID : ISTEX:3F1A4BB0C057CD1E4158F953F9ABABE6B2D75716

Abstract

Objective: We tested the hypothesis that gene delivery of the trophic factor neurturin could preserve motor function and protect nigrostriatal circuitry in hemiparkinsonian monkeys. Methods: 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. Results: 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. Interpretation: 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

Url:
DOI: 10.1002/ana.21032


Affiliations:


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