Intravenous treatment of experimental Parkinson's disease in the mouse with an IgG-GDNF fusion protein that penetrates the blood-brain barrier.
Glial-derived neurotrophic factor (GDNF) is a trophic factor for the nigra-striatal tract in experimental Parkinson's disease (PD). The neurotrophin must be administered by intra-cerebral injection, because GDNF does not cross the blood-brain barrier (BBB). In the present study, GDNF was re-engineered to enable receptor-mediated transport across the BBB following fusion of GDNF to the heavy chain of a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein is designated cTfRMAb-GDNF. This fusion protein had been previously shown to retain low nM binding constants for both the GDNF receptor and the mouse TfR, and to rapidly enter the mouse brain in vivo following intravenous administration. Experimental PD in mice was induced by the intra-striatal injection of 6-hydroxydopamine, and mice were treated with either saline or the cTfRMAb-GDNF fusion protein every other day for 3 weeks, starting 1 h after toxin injection. Fusion protein treatment caused a 44% decrease in apomorphine-induced rotation, a 45% reduction in amphetamine-induced rotation, a 121% increase in the vibrissae-elicited forelimb placing test, and a 272% increase in striatal tyrosine hydroxylase (TH) enzyme activity at 3 weeks after toxin injection. Fusion protein treatment caused no change in TH enzyme activity in either the contralateral striatum or the frontal cortex. In conclusion, following fusion of GDNF to a BBB molecular Trojan horse, GDNF trophic effects in brain in experimental PD are observed following intravenous administration.
Fu
Ailing
A
Department of Medicine, UCLA, Los Angeles, CA 90024, USA.
Zhou
Qing-Hui
QH
Hui
Eric Ka-Wai
EK
Lu
Jeff Zhiqiang
JZ
Boado
Ruben J
RJ
Pardridge
William M
WM
D000818:Animals; D001812:Blood-Brain Barrier; D003342:Corpus Striatum / Q000378:metabolism; D005552:Forelimb / Q000187:drug effects / Q000502:physiology; D007839:Functional Laterality; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D012399:Rotation; D013378:Substantia Nigra / Q000378:metabolism; D014738:Vibrissae / Q000187:drug effects / Q000502:physiology
D051100:Glial Cell Line-Derived Neurotrophic Factor; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins