title: Brain penetrating IgG-erythropoietin fusion protein is neuroprotective following intravenous treatment in Parkinson's disease in the mouse.
abstract: Parkinson's disease (PD) is caused by oxidative stress, and erythropoietin (EPO) reduces oxidative stress in the brain. However, EPO cannot be developed as a treatment for PD, because EPO does not cross the blood-brain barrier (BBB). A brain penetrating form of human EPO has been developed wherein EPO is fused to a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), which is designated as the cTfRMAb-EPO fusion protein. The TfRMAb acts as a molecular Trojan horse to transport the fused EPO into brain via transport on the BBB TfR. Experimental PD was induced in adult mice by the intra-striatal injection of 6-hydroxydopamine, and PD mice were treated with 1mg/kg of the cTfRMAb-EPO fusion protein intravenously (IV) every other day starting 1 h after toxin injection. Following 3weeks of treatment mice were euthanized for measurement of striatal tyrosine hydroxylase (TH) enzyme activity. Mice treated with the cTfRMAb-EPO fusion protein showed a 306% increase in striatal TH enzyme activity, which correlated with improvement in three assays of neurobehavior. The blood hematocrit increased 10% at 2weeks, with no further changes at 3weeks of treatment. A sandwich ELISA showed the immune reaction against the cTfRMAb-EPO fusion protein was variable and low titer. In conclusion, the present study demonstrates that a brain penetrating form of EPO is neuroprotective in PD following IV administration with minimal effects on erythropoiesis.
authors.affiliation: Department of Medicine, UCLA Warren Hall 13-164, 900 Veteran Ave., Los Angeles, CA 90024, USA.
authors.forename: Qing-Hui
authors.initials: QH
authors.lastname: Zhou
authors.forename: Eric Ka-Wai
authors.initials: EK
authors.lastname: Hui
authors.forename: Jeff Zhiqiang
authors.initials: JZ
authors.lastname: Lu
authors.forename: Ruben J
authors.initials: RJ
authors.lastname: Boado
authors.forename: William M
authors.initials: WM
authors.lastname: Pardridge
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D007275:Injections, Intravenous / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007074:Immunoglobulin G; D018696:Neuroprotective Agents; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin