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

Molecular Therapy : the Journal of the American Society of Gene Therapy
Christopher D HerzogRaymond T Bartus

Abstract

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 10(10) to 6 x 10(11) 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. Co...Continue Reading

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Citations

Apr 12, 2011·Current Neurology and Neuroscience Reports·Jennifer Witt, William J Marks
Dec 17, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Eleni A MarkakisD Eugene Redmond
Oct 1, 2011·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Yoland SmithMahlon R DeLong
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