Premium
Delivery of neurturin by AAV2 (CERE‐120)‐mediated gene transfer provides structural and functional neuroprotection and neurorestoration in MPTP‐treated monkeys
Author(s) -
Kordower Jeffrey H.,
Herzog Christopher D.,
Dass Biplob,
Bakay Roy A. E.,
Stansell James,
Gasmi Mehdi,
Bartus Raymond T.
Publication year - 2006
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21032
Subject(s) - neurturin , mptp , substantia nigra , neuroscience , striatum , neuroprotection , dopaminergic , nigrostriatal pathway , biology , neurotrophic factors , dopamine , glial cell line derived neurotrophic factor , receptor , biochemistry
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