The assignee for this patent application is
Reporters obtained the following quote from the background information supplied by the inventors: "Neuromyelitis optica (NMO) is currently the best defined acquired inflammatory demyelinating disorder of the central nervous system (CNS). NMO attacks optic nerves and spinal cord selectively and repeatedly. Clinical, histopathological and immunobiological observations support a pathogenic role for an IgG autoantibody specific for the astrocytic water channel aquaporin-4 (AQP4), and the severity of acute NMO is ameliorated by antibody-depleting therapies.
"In contrast to most inflammatory CNS demyelinating disorders, tissue destruction in NMO is profound. In addition to white matter lesions, NMO characteristically exhibits central necrosis of spinal cord gray matter. Histopathological CNS lesions lack AQP4 and show deposition of IgM and IgG and products of complement activation in a vasculocentric pattern that coincides with the normal distribution of AQP4.
"Until recently, NMO was considered a rare and severe variant of multiple sclerosis (MS). However, the advent of serological testing for AQP4-IgG has revealed that NMO and its inaugural forms are more common than previously recognized. They tend to be misdiagnosed as MS, which lacks a specific biomarker."
In addition to obtaining background information on this patent application, VerticalNews editors also obtained the inventors' summary information for this patent application: "This disclosure provides prognostic methods for evaluating the severity of NMO and NMO-associated diseases as well as methods of treating NMO and NMO-associated diseases.
"In one aspect, methods of providing a prognosis for an individual that has NMO or a NMO-associated disease are provided. Such methods typically include providing a biological sample from the individual; and determining, in vitro, whether or not the biological sample reduces cell surface expression of EAAT2 or reduces uptake of extracellular glutamate compared to a biological sample from an individual that does not have NMO or a NMO-associated disease. Typically, a reduction in cell surface expression of EAAT2 or a reduction in uptake of extracellular glutamate correlates with a prognosis of the individual.
"In another aspect, methods of providing a prognosis for an individual that has NMO or a NMO-associated disease are provided. Such methods generally include providing a biological sample from the individual; contacting the biological sample with primary astrocytes, a differentiated astrocyte-type cell, or a non-astrocytic cell expressing a gene encoding aquaporin-4 or a functional fragment thereof; and determining, in vitro, whether or not the biological sample reduces cell surface expression of EAAT2 or reduces uptake of extracellular glutamate compared to a biological sample from an individual that does not have NMO or a NMO-associated disease. Generally, a reduction in cell surface expression of EAAT2 or a reduction in uptake of extracellular glutamate correlates with a prognosis of the individual.
"Representative biological samples include serum, plasma, cerebrospinal fluid (CSF), and immunoglobulins.
"In still another aspect, methods of providing a prognosis for an individual that has NMO or a NMO-associated disease are provided. Such methods typically include providing a biological sample from the individual; contacting the biological sample with cells or tissues in the presence of aquaporin-4 polypeptides or functional fragments thereof; and determining whether or not complement is activated in the cells. Generally, an activation of complement correlates with a prognosis of the individual. In one embodiment, the aquaporin-4 polypeptides or functional fragments thereof are expressed by the cells.
"In one aspect, methods of treating an individual that has NMO are provided. Such methods can include administering a glutamate receptor antagonist to the individual. Representative glutamate receptor antagonists include 1-amino-3,5-dimethyl-adamantane, 1-aminoadamantane, (+)-3-methoxy-17-methyl-(9.alpha., 13.alpha., 14.alpha.)-morphinan, 17-methyl-9a,13a,14a-morphinan-3-ol, 2-(2-chlorophenyl)-2-methylamino-cyclohexan-l-one, 1-(1-phenylcyclohexyl) piperidine, (.+-.)cis-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride, and 6-(Dimethylamino)-4,4-diphenylheptan-3-one. Such methods can further include administering a compound to the individual that inhibits complement.
"In still another aspect, methods of treating an individual that has NMO are provided. Such methods typically include administering a compound to the individual that inhibits complement. Representative compounds that inhibit complement include Compstatin, APT070 (Mirococept), soluble complement receptor 1 (sCR1), anti-C5 antibody, eculizumab (Soliris.RTM.), and substituted dihydrobenzofurans, spirobenzofuran-2(3H)-cycloalkanes, and their open chain intermediates. Such methods can further include administering a glutamate receptor antagonist to the individual.
"Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the methods and compositions of matter belong. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the methods and compositions of matter, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.
DESCRIPTION OF DRAWINGS
"FIG. 1 is a graph showing the quantitation of membrane cytotoxicity induced by NMO serum and active complement (30 minutes at 37.degree. C.). Results were the average of seven independent experiments each using an individual serum pool from 10-15 different NMO patients or from approximately 350 control patients with miscellaneous disorders.
"FIG. 2 are graphs that demonstrate that, in primary astrocytes, NMO-IgG impaired glutamate uptake or complement activation. (A) Quantitation of membrane permeability after exposure to control or NMO serum. Increase in permeability to propidium iodide (PI)>2 fold by NMO serum required active complement (.DELTA.C'=inactivated complement). (B) Uptake of L-[.sup.3H]glutamate (.+-.Na+-containing buffer) without human serum (open box) or in control (shaded box) or NMO serum (hatched box). Excess unlabeled glutamate (dark box) prevented L-[.sup.3H]glutamate uptake. NMO serum reduced L-[.sup.3H]glutamate uptake by 50%. Experiment (B) was performed twice. All others were performed at least 3 times.
"FIG. 3 demonstrates that expression of aquaporin proteins in HEK-293 cells induced EAAT2 protein expression. Glutamate transport: GFP-AQP4 cells took up approximately 3 fold more L-[.sup.3H]glutamate than vector-transfected cells (note Na+-dependence). All experiments were performed a minimum of two times.
"FIG. 4 shows a flow-chart showing pathways for serological evaluation of patients."
For more information, see this patent application: Lennon, Vanda A.; Hinson, Shannon; Pittock, Sean J. Materials and Methods for Evaluating and Treating Neuromyelitis Optica (Nmo). Filed
Keywords for this news article include: Antibodies, Neurology, Aquaporins, Immunology, Legal Issues, Glutamic Acid, Blood Proteins, Optic Neuritis, Immunoglobulins, Carrier Proteins, Membrane Proteins, Multiple Sclerosis, Glutamate Receptors, Transverse Myelitis, Amino Acid Receptors, Neuromyelitis Optica, Optic Nerve Diseases, Cranial Nerve Diseases.
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