title: Human NgR-Fc decoy protein via lumbar intrathecal bolus administration enhances recovery from rat spinal cord contusion.
abstract: Axonal growth and neurological recovery after traumatic spinal cord injury (SCI) is limited by the presence of inhibitory proteins in myelin, several of which act via the NgR1 protein in neurons. A truncated soluble ligand-binding fragment of NgR1 serves as a decoy and promotes recovery in acute and chronic rodent SCI models. To develop the translational potential of these observations, we created a human sequence-derived NgR1(310)-Fc protein. This protein is active in vitro. When the human NgR1 decoy is administered by continuous intracerebroventricular infusion to rats with a spinal contusion injury at doses of 0.09-0.53 mg/kg/d, neurological recovery is improved. Effective doses double the percentage of rats able to bear weight on their hindlimbs. Next, we considered the half-life and distribution of NgR1(310)-Fc after bolus delivery to the lumbar intrathecal space. The protein is found throughout the neuraxis and has a tissue half-life of approximately 2 days in the rat, and 5 days in the nonhuman primate. At an intermittent, once every 4 day, lumbar bolus dosing schedule of 0.14 mg/kg/d, NgR1(310)-Fc promoted locomotor rat recovery from spinal cord contusion at least as effectively as continuous infusion in open field and grid walking tasks. Moreover, the intermittent lumbar NgR1(310)-Fc treatment increased the growth of raphespinal axons into the lumbar spinal cord after injury. Thus, human NgR1(310)-Fc provides effective treatment for recovery from traumatic SCI in this preclinical model with a simplified administration regimen that facilitates clinical testing.
authors: 1 Program in Cellular Neuroscience, Neurodegeneration & Repair, and Yale University School of Medicine , New Haven, Connecticut.
authors: Xingxing
authors: X
authors: Wang
authors: Kazim
authors: K
authors: Yigitkanli
authors: Chang-Yeon
authors: CY
authors: Kim
authors: Tomoko
authors: T
authors: Sekine-Komo
authors: Dana
authors: D
authors: Wirak
authors: Eric
authors: E
authors: Frieden
authors: Ajay
authors: A
authors: Bhargava
authors: George
authors: G
authors: Maynard
authors: William B J
authors: WB
authors: Cafferty
authors: Stephen M
authors: SM
authors: Strittmatter
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D058851:GPI-Linked Proteins / Q000008:administration & dosage; D006801:Humans; D007278:Injections, Spinal; D009185:Myelin Proteins / Q000008:administration & dosage*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D000070816:Nogo Receptor 1; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000008:administration & dosage*; D011961:Receptors, Fc / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage; D020127:Recovery of Function / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000188:drug therapy*
chemical_list: D058851:GPI-Linked Proteins; D009185:Myelin Proteins; D018696:Neuroprotective Agents; D000070816:Nogo Receptor 1; C486580:RTN4R protein, human; D011956:Receptors, Cell Surface; D011961:Receptors, Fc; D011994:Recombinant Proteins
keywords: Nogo; Nogo receptor; contusion; myelin; pharmacokinetics; translational science; traumatic spinal cord injury