Convection-enhanced delivery of MANF--volume of distribution analysis in porcine putamen and substantia nigra.
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a 20kDa human protein which has both neuroprotective and neurorestorative activity on dopaminergic neurons and therefore may have application for the treatment of Parkinson's Disease. The aims of this study were to determine the translational potential of convection-enhanced delivery (CED) of MANF for the treatment of PD by studying its distribution in porcine putamen and substantia nigra and to correlate histological distribution with co-infused gadolinium-DTPA using real-time magnetic resonance imaging. We describe the distribution of MANF in porcine putamen and substantia nigra using an implantable CED catheter system using co-infused gadolinium-DTPA to allow real-time MRI tracking of infusate distribution. The distribution of gadolinium-DTPA on MRI correlated well with immunohistochemical analysis of MANF distribution. Volumetric analysis of MANF IHC staining indicated a volume of infusion (Vi) to volume of distribution (Vd) ratio of 3 in putamen and 2 in substantia nigra. This study confirms the translational potential of CED of MANF as a novel treatment strategy in PD and also supports the co-infusion of gadolinium as a proxy measure of MANF distribution in future clinical studies. Further study is required to determine the optimum infusion regime, flow rate and frequency of infusions in human trials.
Functional Neurosurgery Research Group, University of Bristol, UK.
N U
NU
Barua
Functional Neurosurgery Research Group, University of Bristol, UK.
A S
AS
Bienemann
Neurological Applications Division, Renishaw PLC., Gloucs., UK.
M
M
Woolley
Functional Neurosurgery Research Group, University of Bristol, UK.
M J
MJ
Wyatt
Neurological Applications Division, Renishaw PLC., Gloucs., UK.
D
D
Johnson
Neurological Applications Division, Renishaw PLC., Gloucs., UK.
O
O
Lewis
Neurological Applications Division, Renishaw PLC., Gloucs., UK.
C
C
Irving
Neurological Applications Division, Renishaw PLC., Gloucs., UK.
G
G
Pritchard
Functional Neurosurgery Research Group, University of Bristol, UK. Electronic address: annub@bristol.ac.uk.
S
S
Gill
D000818:Animals; D018481:Convection; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D057967:Infusions, Intraventricular; D008297:Male; D009414:Nerve Growth Factors / Q000008:administration & dosage*; D011699:Putamen / Q000737:chemistry* / Q000187:drug effects; D013378:Substantia Nigra / Q000737:chemistry* / Q000187:drug effects; D013552:Swine
C099695:MANF protein, human; D009414:Nerve Growth Factors
Convection-enhanced delivery; Mesencephalic astrocyte-derived neurotrophic factor; Parkinson's Disease