Research Article| Volume 357, ISSUE 1-2, P264-269, October 15, 2015

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Convection-enhanced delivery of MANF — Volume of distribution analysis in porcine putamen and substantia nigra

Published:August 05, 2015DOI:


      • Convection-enhanced delivery of MANF in porcine putamen and substantia nigra results in widespread distribution.
      • MANF distribution correlates well with co-infused gadolinium-DTPA visualised with real-time MRI.
      • This study confirms the translational potential of CED of MANF as a novel treatment strategy for Parkinson's Disease.


      Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a 20 kDa 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.


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        • Petrova P.
        • et al.
        MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons.
        J. Mol. Neurosci. 2003; 20: 173-188
        • Hellman M.
        • et al.
        Mesencephalic astrocyte-derived neurotrophic factor (MANF) has a unique mechanism to rescue apoptotic neurons.
        J. Biol. Chem. 2011; 286: 2675-2680
        • Chen Y.C.
        • et al.
        MANF regulates dopaminergic neuron development in larval zebrafish.
        Dev. Biol. 2012; 370: 237-249
        • Yu Y.Q.
        • et al.
        Induction profile of MANF/ARMET by cerebral ischemia and its implication for neuron protection.
        J. Cereb. Blood Flow Metab. 2010; 30: 79-91
        • Lindholm P.
        • et al.
        MANF is widely expressed in mammalian tissues and differently regulated after ischemic and epileptic insults in rodent brain.
        Mol. Cell. Neurosci. 2008; 39: 356-371
        • Voutilainen M.H.
        • et al.
        Mesencephalic astrocyte-derived neurotrophic factor is neurorestorative in rat model of Parkinson's disease.
        J. Neurosci. 2009; 29: 9651-9659
        • Nutt J.G.
        • et al.
        Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD.
        Neurology. 2003; 60: 69-73
        • Lang A.E.
        • et al.
        Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease.
        Ann. Neurol. 2006; 59: 459-466
        • Salvatore M.F.
        • et al.
        Point source concentration of GDNF may explain failure of phase II clinical trial.
        Exp. Neurol. 2006; 202: 497-505
        • Richardson R.M.
        • et al.
        Interventional MRI-guided putaminal delivery of AAV2-GDNF for a planned clinical trial in Parkinson's disease.
        Mol. Ther. 2011; 19: 1048-1057
        • Bobo R.H.
        • et al.
        Convection-enhanced delivery of macromolecules in the brain.
        Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2076-2080
        • Barua N.U.
        • Gill S.S.
        • Love S.
        Convection-enhanced drug delivery to the brain: therapeutic potential and neuropathological considerations.
        Brain Pathol. 2014; 24: 117-127
        • Bienemann A.
        • et al.
        The development of an implantable catheter system for chronic or intermittent convection-enhanced delivery.
        J. Neurosci. Methods. 2012; 203: 284-291
        • Gill T.
        • et al.
        In vitro and in vivo testing of a novel recessed-step catheter for reflux-free convection-enhanced drug delivery to the brain.
        J. Neurosci. Methods. 2013; 219: 1-9
        • Barua N.U.
        • et al.
        Intrastriatal convection-enhanced delivery results in widespread perivascular distribution in a pre-clinical model.
        Fluids Barriers CNS. 2012; 9: 2
        • Hoque N.
        • et al.
        Validation of a neuropathology score using quantitative methods to evaluate brain injury in a pig model of hypoxia ischaemia.
        J. Neurosci. Methods. 2014; 230: 30-36
        • Kornum B.R.
        • et al.
        The effect of the inter-phase delay interval in the spontaneous object recognition test for pigs.
        Behav. Brain Res. 2007; 181: 210-217
        • Ziegler D.A.
        • et al.
        Substantia nigra volume loss before basal forebrain degeneration in early Parkinson disease.
        JAMA Neurol. 2013; 70: 241-247
        • Yin D.
        • et al.
        Striatal volume differences between non-human and human primates.
        J. Neurosci. Methods. 2009; 176: 200-205