title: Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson's disease.
abstract: Clinical trials involving direct infusion of neurotrophic therapies for Parkinson's disease (PD) have suffered from poor coverage of the putamen. The planned use of a novel interventional-magnetic resonance imaging (iMRI) targeting system for achieving precise, real-time convection-enhanced delivery in a planned clinical trial of adeno-associated virus serotype 2 (AAV2)-glial-derived neurotrophic factor (GDNF) in PD patients was modeled in nonhuman primates (NHP). NHP received bilateral coinfusions of gadoteridol (Gd)/AAV2-GDNF into two sites in each putamen, and three NHP received larger infusion volumes in the thalamus. The average targeting error for cannula tip placement in the putamen was <1 mm, and adjacent putamenal infusions were distributed in a uniform manner. GDNF expression patterns in the putamen were highly correlated with areas of Gd distribution seen on MRI. The distribution volume to infusion volume ratio in the putamen was similar to that in the thalamus, where larger infusions were achieved. Modeling the placement of adjacent 150 and 300 µl thalamic infusions into the three-dimensional space of the human putamen demonstrated coverage of the postcommissural putamen, containment within the striatum and expected anterograde transport to globus pallidus and substantia nigra pars reticulata. The results elucidate the necessary parameters for achieving widespread GDNF expression in the putamenal motor area and afferent substantia nigra of PD patients.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94143-0112, USA. richardsonma@neuosurg.usf.edu
authors.forename: R Mark
authors.initials: RM
authors.lastname: Richardson
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Kells
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Rosenbluth
authors.forename: Ernesto Aguilar
authors.initials: EA
authors.lastname: Salegio
authors.forename: Massimo S
authors.initials: MS
authors.lastname: Fiandaca
authors.forename: Paul S
authors.initials: PS
authors.lastname: Larson
authors.forename: Philip A
authors.initials: PA
authors.lastname: Starr
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Martin
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Federoff
authors.forename: John R
authors.initials: JR
authors.lastname: Forsayeth
authors.forename: Krystof S
authors.initials: KS
authors.lastname: Bankiewicz
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D000229:Dependovirus / Q000235:genetics*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy*; D011699:Putamen / Q000378:metabolism*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor