Transgene expression, bioactivity, and safety of CERE-120 (AAV2-neurturin) following delivery to the monkey striatum

被引：67

作者：

Herzog, Christopher D. ^{[1
]}

Dass, Biplob ^{[2
]}

Gasmi, Mehdi ^{[1
]}

Bakay, Roy ^{[3
]}

Stansell, James E. ^{[2
]}

Tuszynski, Mark ^{[4
]}

Bankiewicz, Krystof ^{[5
]}

Chen, Er-Yun ^{[2
]}

Chu, Yaping ^{[2
]}

Bishop, Kathie ^{[1
]}

Kordower, Jeffrey H. ^{[2
]}

Bartus, Raymond T. ^{[1
]}

机构：

[1] Ceregene Inc, San Diego, CA 92121 USA

[2] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA

[3] Rush Univ, Med Ctr, Dept Neurosurg, Chicago, IL 60612 USA

[4] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[5] Univ Calif San Francisco, Dept Neurosurg, San Francisco, CA 94143 USA

来源：

MOLECULAR THERAPY | 2008年 / 16卷 / 10期

关键词：

D O I：

10.1038/mt.2008.170

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Neurturin (NTN) is a neurotrophic factor for dopaminergic neurons that may be therapeutic for patients with Parkinson's disease (PD). As a crucial component in a series of nonclinical translational studies aimed at testing whether CERE-120 should advance into clinical trials in PD subjects, we characterized the expression, bioactivity and safety of CERE-120, an adeno-associated virus type-2 (AAV2) vector encoding NTN, following delivery to the striatum of nonhuman primates. Monkeys received bilateral injections of CERE-120 across a tenfold range of doses (6 x 1010 to 6 x 1011 vector genomes per animal) or formulation buffer (FB) control. We report here, for the first time, a dose-related: increase in NTN protein expression within the striatum and substantia nigra (SN) pars compacta of nonhuman primates; increase in nigrostriatal tyrosine hydroxylase (TH), (the rate-limited enzyme for dopamine); and activation of phosphorylated signal-regulated kinase (a common neurotrophic signaling event). Additionally, extensive toxicology testing revealed no adverse effects of CERE-120 on in-life measures, neurotoxicity (in any site throughout the brain) or systemic pathology (in any organ or tissue) across the tenfold range of doses. Collectively, these data provide substantial novel evidence for the potential utility of CERE-120 as a novel treatment for PD and support ongoing clinical trials testing CERE-120 in PD patients.

引用

页码：1737 / 1744

页数：8

共 36 条

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