title: Intravitreal delivery of human NgR-Fc decoy protein regenerates axons after optic nerve crush and protects ganglion cells in glaucoma models.
abstract: OBJECTIVE
  Glaucoma is a major cause of vision loss due to retinal ganglion cell (RGC) degeneration. Therapeutic intervention controls increased IOP, but neuroprotection is unavailable. NogoReceptor1 (NgR1) limits adult central nervous system (CNS) axonal sprouting and regeneration. We examined NgR1 blocking decoy as a potential therapy by defining the pharmacokinetics of intravitreal NgR(310)-Fc, its promotion of RGC axonal regeneration following nerve crush, and its neuroprotective effect in a microbead glaucoma model.
  
  
  METHODS
  Human NgR1(310)-Fc was administered intravitreally, and levels were monitored in rat vitreal humor and retina. Axonal regeneration after optic nerve crush was assessed by cholera toxin β anterograde labeling. In a microbead model of glaucoma with increased IOP, the number of surviving and actively transporting RGCs was determined after 4 weeks by retrograde tracing with Fluro-Gold (FG) from the superior colliculus.
  
  
  RESULTS
  After intravitreal bolus administration, the terminal half-life of NgR1(310)-Fc between 1 and 7 days was approximately 24 hours. Injection of 5 μg protein once per week after optic nerve crush injury significantly increased RGCs with regenerating axons. Microbeads delivered to the anterior chamber increased pressure, and caused 15% reduction in FG-labeled RGCs of control rats, with a 40% reduction in large diameter RGCs. Intravitreal treatment with NgR1(310)-Fc did not reduce IOP, but maintained large diameter RGC density at control levels.
  
  
  CONCLUSIONS
  Human NgR1(310)-Fc has favorable pharmacokinetics in the vitreal space and rescues large diameter RGC counts from increased IOP. Thus, the NgR1 blocking decoy protein may have efficacy as a disease-modifying therapy for glaucoma.
authors: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, Connecticut, United States Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, United States.
authors: Xingxing
authors: X
authors: Wang
authors: Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, United States.
authors: Jun
authors: J
authors: Lin
authors: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, Connecticut, United States Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, United States.
authors: Alexander
authors: A
authors: Arzeno
authors: Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, United States.
authors: Jin Young
authors: JY
authors: Choi
authors: Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, United States.
authors: Juliann
authors: J
authors: Boccio
authors: Axerion Therapeutics, Branford, Connecticut, United States.
authors: Eric
authors: E
authors: Frieden
authors: Shakti BioResearch, Woodbridge, Connecticut, United States.
authors: Ajay
authors: A
authors: Bhargava
authors: Axerion Therapeutics, Branford, Connecticut, United States.
authors: George
authors: G
authors: Maynard
authors: Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, United States.
authors: James C
authors: JC
authors: Tsai
authors: Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, Connecticut, United States Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, United States.
authors: Stephen M
authors: SM
authors: Strittmatter
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D058851:GPI-Linked Proteins / Q000008:administration & dosage; D005901:Glaucoma / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects*; D000070156:Nogo Receptors; D009900:Optic Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020221:Optic Nerve Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000008:administration & dosage*; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology
chemical_list: D058851:GPI-Linked Proteins; D000070156:Nogo Receptors; C474328:RTN4RL1 protein, human; D011956:Receptors, Cell Surface
keywords: glaucoma; optic neuropathy; regeneration
references: Nature. 2000 Jan 27;403(6768):434-9
references: 10667796
references: J Biol Chem. 2011 May 20;286(20):18026-36
references: 21454605
references: Invest Ophthalmol Vis Sci. 2000 Mar;41(3):741-8
references: 10711689
references: Nature. 2001 Jan 18;409(6818):341-6
references: 11201742
references: Nature. 2002 Jun 27;417(6892):941-4
references: 12068310
references: Science. 2002 Aug 16;297(5584):1190-3
references: 12089450
references: J Neurosci. 2002 Oct 15;22(20):8876-83
references: 12388594
references: J Neurosci. 2003 Feb 15;23(4):1416-23
references: 12598630
references: Neuron. 2003 Apr 24;38(2):187-99
references: 12718854
references: J Cell Biol. 2003 Jul 21;162(2):233-43
references: 12860969
references: J Neurosci. 2004 Jul 7;24(27):6209-17
references: 15240813
references: Brain Res. 2004 Aug 20;1018(1):111-8
references: 15262212
references: Neuron. 2004 Oct 28;44(3):439-51
references: 15504325
references: Brain Res. 1993 Feb 5;602(2):304-17
references: 8448673
references: Neuron. 1994 Sep;13(3):757-67
references: 7522484
references: Invest Ophthalmol Vis Sci. 2011 Oct;52(11):8374-80
references: 21948553
references: Ann Neurol. 2011 Nov;70(5):805-21
references: 22162062
references: Exp Neurol. 2012 Sep;237(1):55-69
references: 22728374
references: Nat Protoc. 2012 Nov;7(11):1983-95
references: 23060243
references: Proc Natl Acad Sci U S A. 2012 Oct 16;109 Suppl 2:17213-20
references: 23045690
references: Neuron. 2013 Mar 6;77(5):859-66
references: 23473316
references: Curr Opin Neurobiol. 2014 Aug;27:53-60
references: 24632308
references: J Neurotrauma. 2014 Dec 15;31(24):1955-66
references: 24964223
references: Neuron. 1994 Oct;13(4):805-11
references: 7524558
references: J Neurosci. 2004 Nov 17;24(46):10511-20
references: 15548666
references: Bull World Health Organ. 2004 Nov;82(11):887-8
references: 15640929
references: Mol Cell Neurosci. 2005 May;29(1):26-39
references: 15866044
references: J Neurosci. 2005 Jun 1;25(22):5298-304
references: 15930377
references: Eur J Neurosci. 2005 Aug;22(3):587-94
references: 16101740
references: Science. 2005 Sep 30;309(5744):2222-6
references: 16195464
references: Curr Eye Res. 2005 Nov;30(11):1025-31
references: 16282136
references: Invest Ophthalmol Vis Sci. 2006 May;47(5):1968-74
references: 16639004
references: Exp Eye Res. 2006 Aug;83(2):429-37
references: 16682027
references: Philos Trans R Soc Lond B Biol Sci. 2006 Sep 29;361(1473):1593-610
references: 16939977
references: Ann Neurol. 2006 Nov;60(5):540-9
references: 16958113
references: J Biol Chem. 2007 Feb 23;282(8):5715-25
references: 17189258
references: Exp Neurol. 2007 May;205(1):230-40
references: 17359977
references: Eur J Neurosci. 2007 Jun;25(11):3339-46
references: 17553002
references: Neuroscientist. 2007 Oct;13(5):454-69
references: 17901255
references: Exp Eye Res. 2008 May;86(5):798-806
references: 18394603
references: Science. 2008 Nov 7;322(5903):967-70
references: 18988857
references: J Neurosci. 2009 May 13;29(19):6285-95
references: 19439606
references: J Neurosci. 2009 Dec 2;29(48):15266-76
references: 19955379
references: Cell Mol Neurobiol. 2009 Dec;29(8):1143-51
references: 19396539
references: Invest Ophthalmol Vis Sci. 2010 Mar;51(3):1747-54
references: 19875669
references: J Neurosci. 2010 Sep 15;30(37):12432-45
references: 20844138
references: J Neuroophthalmol. 2010 Dec;30(4):347-60
references: 21107123
references: Lancet. 2011 Apr 16;377(9774):1367-77
references: 21453963
references: Nature. 2000 Jan 27;403(6768):439-44
references: 10667797