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

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