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.
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 naïve 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.


CONCLUSIONS
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.
Herzog
Christopher D
CD
Ceregene, Inc., San Diego, California, USA.
Brown
Lamar
L
Gammon
Dawn
D
Kruegel
Brian
B
Lin
Richard
R
Wilson
Alistair
A
Bolton
Ariadne
A
Printz
Marie
M
Gasmi
Mehdi
M
Bishop
Kathie M
KM
Kordower
Jeffrey H
JH
Bartus
Raymond T
RT
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002452:Cell Count; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D008137:Longitudinal Studies; D008253:Macaca mulatta; D051101:Neurturin / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy*; D013116:Spinal Cord / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015740:Calcitonin Gene-Related Peptide; D048049:Extracellular Signal-Regulated MAP Kinases; D051101:Neurturin; D014446:Tyrosine 3-Monooxygenase; D014763:Viral Matrix Proteins; C067980:CD68 antigen, human; D000097382:CD68 Molecule