A Go on NOGO: Promising Therapy for CNS Disease and Injury

So has anything here been put into clinical practice after 15 years studying this? We need axonal regeneration. Is this a piece of the stroke strategy? WHOM is making sure this gets translated into viable clinical interventions?

A Go on NOGO: Promising Therapy for CNS Disease and Injury

Cecilia Reyes and Yaroslav Voronin
Department of Biology
Lake Forest College
Lake Forest, Illinois 60045

Abstract

Mammals  have  evolved  with  a  limited  capacity  to  regenerate  neurons  in  the  CNS.  Damage  to  the  CNS  by  traumatic  injury,  stroke and neurodegenerative disorders can result in permanent loss of  sensory,  motor,  and  cognitive  functions.    Fifteen  years  ago,  my lab began studying the inhibitory mechanisms in damaged CNS.  We have identified the myelin-associated protein Nogo-A as a key player in  sprouting  inhibition.  Nogo-A,  as  well  as  two  other  inhibitory  proteins, MAG and OMgp, bind to the nogo-66 receptor (NgR) to inhibit axonal regeneration in the CNS.  We identified two mechanisms with neurons  that  promote  Nogo-based  CNS  inhibition:  the  rho-ROCK  kinase  pathway  that  is  selectively  activated  by  NgR,  and  the  integrin-actin pathway that is activated by a 66-amino-acid residue on Nogo-A.  While genetic and chemical disruption of NgR ligands (nogo-A, MAG and OMgp) has resulted in poor regeneration after injury, manipulation of NgR has shown promising therapeutic value in both in vivo and in vitro. Therapeutic administration of NgR(310)ecto-Fc protein, an NgR antagonist, in tissue and mouse models can neutralize the inhibitory effects of the three NgR ligands and has proven beneficial in
promoting motor function after spinal cord injury and stroke. Finally, we have found that inhibiting Nogo-A in ALS and Alzheimer’s disease models reduces pathological characteristics, indicating that manipulating Nogo-NgR based inhibition holds great promise for CNS injury
and neurodegenerative disease. 

Effects of Postinfarct Myelin-Associated Glycoprotein Antibody Treatment on Motor Recovery and Motor Map Plasticity in Squirrel Monkeys

Send out for more research on this and what the translational protocol would look like.
http://stroke.ahajournals.org/content/early/2015/04/30/STROKEAHA.114.008088.abstract?sid=ec499f51-44bc-4180-9fe6-0e74006f3dae

1. Scott Barbay, PhD,
2. Erik J. Plautz, PhD,
3. Elena Zoubina, PhD,
4. Shawn B. Frost, PhD,
5. Steven C. Cramer, MD and
6. Randolph J. Nudo, PhD

+ Author Affiliations

1. From the Department of Molecular and Integrative Physiology, Landon Center on Aging, University of Kansas Medical Center (S.B., E.J.P., E.Z., S.B.F., R.J.N.); and Department of Neurology and Department of Anatomy and Neurobiology, University of California, Irvine (S.C.C.).

+ Author Notes

• Current address for E.J.P.: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas.
• Current address for E.Z.: Department of Neurology, Harvard Medical School, Boston, MA.

1. Correspondence to Randolph J. Nudo, PhD, University of Kansas Medical Center, Landon Center on Aging, MS 1005, 3901 Rainbow Blvd, Kansas City, KS 66160. E-mail rnudo@kumc.edu

Abstract

Background and Purpose—New insights into the brain’s ability to reorganize after injury are beginning to suggest novel restorative therapy targets. Potential therapies include pharmacological agents designed to promote axonal growth. The purpose of this study was to test the efficacy of one such drug, GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule, myelin-associated glycoprotein, to facilitate recovery of motor skills in a nonhuman primate model of ischemic cortical damage.

Methods—Using a between-groups repeated-measures design, squirrel monkeys were randomized to 1 of 2 groups: an experimental group received intravenous GSK249320 beginning 24 hours after an ischemic infarct in motor cortex with repeated dosages given at 1-week intervals for 6 weeks and a control group received only the vehicle at matched time periods. The primary end point was a motor performance index based on a distal forelimb reach-and-retrieval task. Neurophysiological mapping techniques were used to determine changes in spared motor representations.

Results—All monkeys recovered to baseline motor performance levels by postinfarct day 16. Functional recovery in the experimental group was significantly facilitated on the primary end point, albeit using slower movements. At 7 weeks post infarct, motor maps in the spared ventral premotor cortex in the experimental group decreased in area compared with the control group.

Conclusions—GSK249320, initiated 24 hours after a focal cortical ischemic infarct, facilitated functional recovery. Together with the neurophysiological data, these results suggest that GSK249320 has a substantial biological effect on spared cortical tissue. However, its mechanisms of action may be widespread and not strictly limited to peri-infarct cortex and nearby premotor areas.

The molecular mechanisms of Nogo signaling

Another great dissertation, only 24 pages for your doctor to figure out.

The molecular mechanisms of  Nogo signaling

Summary    3
Inhibition of axon regeneration in the CNS    4
Astrocytes and the glial scar    4
Myelin associated inhibitors    4
Nogo, the principal myelin associated inhibitor    5
Nogo is a member of the RTN protein family    6
Nogo structure    6
The stucture of the Nogo RTN domain    6
Nogo-A and B specific domains    7
Membrane topology    7
Nogo receptors    8
Downstream signaling in the CNS    9
Activation of RhoA, the second messenger for cytoskeletal dynamics    9
The RhoA-ROCK pathway and its downstream effectors    10
Activation of Ca2+ and cAMP signaling pathways    11
Signal transduction downstream of Ca2+ and cAMP mediates a switch in axonal response    12
Downstream effectors of cAMP influence neurite outgrowth    12
cAMP levels control regenerative capacity after a preconditioning lesion and during maturation    13
Nogo functions in the nervous system    13
Nogo-A hampers axonal regeneration after CNS injury    13
Roles of Nogo in the developing CNS    14
Nogo regulates plasticity of the adult CNS    15
Nogo-B and C in myelin associated inhibition    15
Specific functions of Nogo-B and C    15
Discussion    17
List of Abbreviations    18
Refrences    19

Summary

Damage to the adult central nervous system often leads to permanent loss of function. Several inhibitory factors specific for the CNS prevent regeneration of severed axons and network connectivity is lost permanently. One obstacle for regenerating neurons is formed by myelin associated inhibitors; the proteins Nogo, MAG and OMgp, which are expressed by myelinating oligodendrocytes in the CNS. Of these three, Nogo is believed to be the main mediator of growth inhibition in the adult CNS. The nogo gene gives rise to three protein products, the Nogo isoforms A, B and C. Nogo-A the isoform that functions as an inhibitor for neuronal growth, during development Nogo-A is involved in axonal guidance and in the uninjured adult CNS Nogo regulates functional plasticity. Nogo-B and C are less well studied jet some specific functions are known. Signaling by Nogo-A involves multiple receptors that activate parallel cascades of downstream effectors. These signaling pathways ultimately lead to a halt in axon growth. Signaling commences when Nogo binds to one of its receptors. To date, two receptors for Nogo-A have been identified, NgR1 and co-receptors LINGO-1 and p75 or TROY, and the receptor PirB. Via these receptors, multiple signaling routes involving RhoA, cAMP and Ca²⁺ are activated. These second messengers and their downstream effectors determine growth direction and induce growth cone collapse. In vitro studies of Nogo function confirm its role as an inhibitor of neuronal growth and regeneration. However, in vivo studies of Nogo function in animals lacking one or more Nogo isoforms show inconsistent regeneration phenotypes. In contrast, treatment with function blocking anti-Nogo antibodies has profound and consistent positive effects on regeneration of the CNS and recovery of motor function. These Nogo blocking antibodies have great therapeutic potential and are currently being evaluated in clinical trials. The antibodies may soon be available to patients with CNS injuries and greatly improve their rehabilitation.

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