EXPRESSION, BIOACTIVITY, AND SAFETY 1 YEAR AFTER ADENO-ASSOCIATED VIRAL VECTOR TYPE 2-MEDIATED DELIVERY OF NEURTURIN TO THE MONKEY NIGROSTRIATAL SYSTEM SUPPORT CERE-120 FOR PARKINSON'S DISEASE

被引：58

作者：

Herzo, Christopher D. ^{[1
]}

Brown, Lamar ^{[1
]}

Gammon, Dawn ^{[1
]}

Kruegel, Brian ^{[1
]}

Lin, Richard ^{[1
]}

Wilson, Alistair ^{[1
]}

Bolton, Ariadne ^{[1
]}

Printz, Marie ^{[1
]}

Gasmi, Mehdi ^{[1
]}

Bishop, Kathie M. ^{[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

来源：

NEUROSURGERY | 2009年 / 64卷 / 04期

关键词：

Adeno-associated virus; CERE-120; Gene therapy; Neurotrophic factor; Neurturin; Parkinson's disease; NEUROTROPHIC FACTOR INCREASES; AGED RHESUS-MONKEYS; PHASE-I TRIAL; INTRAPUTAMENAL INFUSION; DOPAMINERGIC-NEURONS; STRIATAL DELIVERY; PRIMATE MODELS; GENE-THERAPY; LESION MODEL; AAV2; VECTOR;

D O I：

10.1227/01.NEU.0000340682.06068.01

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

OBJECTIVE: Parkinson's disease is characterized by profound motor deficits that result mainly as a consequence of degeneration of midbrain dopaminergic neurons. No current therapy slows or halts disease progression. Neurturin (NTN) and glial cell line-derived neurotrophic factor have potent neuroprotective and neurorestorative effects on dopaminergic neurons, but their use in treating Parkinson's disease has been limited by significant delivery obstacles. In this study, we examined the long-term expression, bioactivity, and safety/tolerability of CERE-120, an adeno-associated virus type 2 vector encoding human NTN, after bilateral stereotactic delivery to the striatum of nonhuman primates. METHODS: Twelve naive rhesus macaques received bilateral stereotactic injections of 1 of 2 CERE-120 doses or vehicle to the caudate and putamen. Neurological and clinical parameters were monitored for up to 1 year postadministration, after which animals were sacrificed for histological analyses. RESULTS: Dose-related NTN expression was observed at 1 year and was associated with enhanced tyrosine hydroxylase immunolabeling in the striatum, hypertrophy of tyrosine hydroxylase-positive cells in the substantia nigra, and induction of extracellular signal-regulated kinase signaling in the substantia nigra. Extensive, formal analyses, conducted in accordance with Good Laboratory Practice Regulations, across multiple time points revealed no evidence of clinical, neurological, or systemic toxicity. CONCLUSION: The present study provides evidence of long-term expression and bioactivity of NTN on the dopaminergic nigrostriatal system after bilateral stereotactic delivery of CERE-120 to the striatum. Furthermore, no evidence of any adverse effects for up to 1 year postadministration was observed. These findings reveal a wide safety margin for CERE-120 and collectively support the ongoing clinical testing of the efficacy and safety of CERE-120 in patients with Parkinson's disease.

引用

页码：602 / 612

页数：11

共 34 条

[1] Long-term clinical improvement in MPTP-lesioned primates after gene therapy with AAV-hAADC [J].