Safety and tolerability of magnetic resonance imaging-guided convection-enhanced delivery of AAV2-hAADC with a novel delivery platform in nonhuman primate striatum.
Degeneration of nigrostriatal neurons in Parkinson's disease (PD) causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa (l-DOPA) into dopamine in the striatum. Because loss of this enzyme appears to be a major driver of progressive impairment of response to the mainstay drug, l-DOPA, one promising approach has been to use gene therapy to restore AADC activity in the human putamen and thereby restore normal l-DOPA response in patients with PD. An open-label phase I clinical trial of this approach in patients with PD provided encouraging signs of improvement in Unified Parkinson's Disease Rating Scale scores and reductions in antiparkinsonian medications. However, such improvement was modest compared with the results previously reported in parkinsonian rhesus macaques. The reason for this discrepancy may have been that the relatively small volume of vector infused in the clinical study restricted the distribution of AADC expression, such that only about 20% of the postcommissural putamen was covered, as revealed by l-[3-(18)F]-α-methyltyrosine-positron emission tomography. To achieve more quantitative distribution of vector, we have developed a visual guidance system for parenchymal infusion of AAV2. The purpose of the present study was to evaluate the combined magnetic resonance imaging-guided delivery system with AAV2-hAADC under conditions that approximate the intended clinical protocol. Our data indicate that this approach directed accurate cannula placement and effective vector distribution without inducing any untoward effects in nonhuman primates infused with a high dose of AAV2-hAADC.
Department of Neurological Surgery, University of California San Francisco , San Francisco, CA 94103, USA.
Waldy
W
San Sebastian
R Mark
RM
Richardson
Adrian P
AP
Kells
Clementine
C
Lamarre
John
J
Bringas
Philip
P
Pivirotto
Ernesto A
EA
Salegio
Stephen J
SJ
Dearmond
John
J
Forsayeth
Krystof S
KS
Bankiewicz
D000818:Animals; D002404:Catheterization; D002421:Caudate Nucleus / Q000201:enzymology; D003342:Corpus Striatum / Q000201:enzymology*; D000229:Dependovirus / Q000235:genetics*; D004296:Dopa Decarboxylase / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D011699:Putamen / Q000201:enzymology / Q000473:pathology; D013238:Stereotaxic Techniques; D019076:Transgenes
D004296:Dopa Decarboxylase