Parkinson's disease (PD) affects 1 million people in the U.S., and is a degenerative disease caused by the loss of brain cells in the nigral-striatal tract. The most potent protective factor for this area of the brain is the neurotrophin, glial derived neurotrophic factor (GDNF). However, GDNF drug development in PD has failed, because the neurotrophin does not cross the blood-brain barrier (BBB). Consequently, the GDNF was administered to patients with PD via a trans-cranial drug delivery system that does not effectively deliver the drug to the part of the brain involved in PD. The present research will genetically engineer a new form of GDNF that is enabled to cross the BBB via receptor-mediated transport. The PI has previously genetically engineered a chimeric MAb against the mouse transferrin receptor (TfR), designated cTfRMAb, that crosses the BBB in the blood-to-brain direction via receptor-mediated transport on the mouse BBB TfR. In addition, the PI has genetically engineered, and expressed a fusion protein of GDNF and the cTfRMAb, which is designated the cTfRMAb-GDNF fusion protein. The bi-functionality of the fusion protein was verified in transient expression experiments. The present research will produce a permanently transfected host cell line using Chinese hamster ovary (CHO) cells that secrete the cTfRMAb-GDNF fusion protein in high amounts so that 200 mg of the fusion protein can be produced. This fusion protein will then be used for pharmacokinetics studies in the mouse, for time response and dose response efficacy studies in an experimental mouse model of PD using C57Bl/6 mice lesioned with intra-cranial 6- hydroxydopmaine. In addition a toxicity study will be performed where male and female C57Bl/6 mice are treated chronically with the cTfRMAb-GDNF fusion protein;the histology of brain and other major organs will then be examined. The formation of anti-fusion protein antibodies will be examined using a novel sandwich ELISA. The drug efficacy in experimental PD will be validated with rotation behavior measurements, and assays of striatal tyrosine hydroxylase. This research will provide the necessary pre-clinical pharmacology to support an IND filing for the treatment of humans with PD using genetically engineered forms of GDNF that cross the BBB via receptor-mediated transport.
Parkinson's disease (PD) affects 1 million people in the U.S. The most potent form of treatment of PD is a neurotrophin called GDNF;however, GDNF does not cross the blood-brain barrier (BBB). The present research will test in experimental PD in mice the efficacy of a new form of GDNF, wherein the neurotrophin is re-engineered as a fusion protein with a monoclonal antibody that crosses the BBB via receptor-mediated transport.
|Sumbria, Rachita K; Boado, Ruben J; Pardridge, William M (2013) Combination stroke therapy in the mouse with blood-brain barrier penetrating IgG-GDNF and IgG-TNF decoy receptor fusion proteins. Brain Res 1507:91-6|
|Zhou, Qing-Hui; Hui, Eric Ka-Wai; Lu, Jeff Zhiqiang et al. (2011) Brain penetrating IgG-erythropoietin fusion protein is neuroprotective following intravenous treatment in Parkinson's disease in the mouse. Brain Res 1382:315-20|
|Zhou, Qing-Hui; Boado, Ruben J; Hui, Eric Ka-Wai et al. (2011) Chronic dosing of mice with a transferrin receptor monoclonal antibody-glial-derived neurotrophic factor fusion protein. Drug Metab Dispos 39:1149-54|
|Zhou, Qing-Hui; Sumbria, Rachita; Hui, Eric Ka-Wai et al. (2011) Neuroprotection with a brain-penetrating biologic tumor necrosis factor inhibitor. J Pharmacol Exp Ther 339:618-23|
|Zhou, Qing-Hui; Boado, Ruben J; Lu, Jeff Zhiqiang et al. (2010) Monoclonal antibody-glial-derived neurotrophic factor fusion protein penetrates the blood-brain barrier in the mouse. Drug Metab Dispos 38:566-72|
|Fu, Ailing; Zhou, Qing-Hui; Hui, Eric Ka-Wai et al. (2010) Intravenous treatment of experimental Parkinson's disease in the mouse with an IgG-GDNF fusion protein that penetrates the blood-brain barrier. Brain Res 1352:208-13|