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Treatment of neuroinflammatory disease

A technology for inflammatory diseases and therapeutic agents, applied in the field of treatment of neuroinflammatory diseases, can solve problems such as involvement, life-threatening side effects, etc.

Pending Publication Date: 2020-03-06
THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Natalizumab, a humanized antibody against α4 integrin, is the most potent therapeutic agent but suffers from severe life-threatening side effects

Method used

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  • Treatment of neuroinflammatory disease
  • Treatment of neuroinflammatory disease
  • Treatment of neuroinflammatory disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] Single-cell analysis reveals differential molecular signatures in myeloid cells from contrasting neuroinflammation models relative to neurodegeneration models

[0121] Two poles are the objects of greater attention in brain pathology: neuroinflammation versus neurodegeneration. Here, we used single-cell mass cytometry (CyToF), which was performed together with unbiased data analysis to compare experimental autoimmune encephalomyelitis ( EAE) mouse model, a system-wide analysis of the immune response in the R6 / 2 mouse model of Huntington's disease (HD) as a neurodegenerative disorder. We identified three populations of myeloid cells that are specific to the central nervous system (CNS) and are present in both neuroinflammatory disorders (EAE) and neurodegenerative disorders (HD). Blood-derived monocytes, the counterparts of CNS-resident myeloid cells, consisted of five subpopulations and were detected in the case of EAE but not in HD. Single-cell analysis revealed larg...

Embodiment 2

[0200] Overview of Myeloid Cell Populations

[0201] The phenotypes of the myeloid cell populations discussed herein are summarized in Table 4. Populations A, B and C correspond to microglia. These populations are equivalent to CD45 medium, CD11b+ cells in the human brain.

[0202] In EAE and MS diseases, as well as many inflammatory disorders, there is an infiltration of monocytes from the peripheral blood. We have identified five monocyte populations, referred to herein as D, E, F, H, G, in the central nervous system of EAE mice. In humans, these populations correspond to CD11b+CD14+CD16+ monocytes. Cytokine expression profiles in the context of these populations showed that at the onset or peak of EAE disease, a percentage of these cells expressed multiple inflammatory cytokines compared to a healthy state in which cells expressed only one cytokine ( TNF-α+GMCSF).

[0203] Table 4

[0204]

Embodiment 3

[0206] amyotrophic lateral sclerosis

[0207] Our previous studies and others have demonstrated that microglia are the only myeloid cells in the brain and spinal cord of mSOD1 mice, a murine ALS disease model, and that there is no infiltration of myeloid cells from the peripheral blood (Ajami et al. 2007) Nature Neuroscience 10:1538-1543; Chiu et al. (2013) Cell Reports 4(2):385-401). Furthermore, several studies have demonstrated that microglia are involved in the pathogenesis of ALS, and that limiting expression of mutant SOD in microglia will delay degeneration and prolong the survival of motor mSOD-expressing motor neurons (Clement et al. (2003) Science 302:113-117; Lino et al. (2002) The Journal of Neuroscience 22(12):4825-4832).

[0208] Such as Figure 13 In mice overexpressing human mutant superoxide dismutase 1 (mSOD), a model of murine ALS, there is an increased expression of CD49e in the microglial population at the end-stage of the disease, as shown in . We comp...

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Abstract

Provided herein are methods and compositions for treating inflammatory diseases by administering to the subject an effective dose of an anti-alpha5 agent. Specifically, the methods are provided for the treatment of inflammatory diseases, including neuroinflammatory disease such as, neuroinflammatory demyelinating autoimmune diseases including multiple sclerosis (MS) and neuromyelitis optica (NMO),as well as the treatment of amyotrophic lateral sclerosis (ALS).

Description

[0001] cross reference [0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 512,457, filed May 30, 2017, which is hereby incorporated by reference in its entirety. Background technique [0003] Multiple sclerosis (MS) is the most prevalent inflammatory disease of the brain and spinal cord in Europe and North America. More than one million people are affected worldwide, including 400,000 in the United States. Symptoms often begin in young adulthood and include motor paralysis, visual disturbance and blindness, bowel and bladder incontinence, sensory loss, and incoordination and ataxia. In the United States, the first-line approved therapies are glatiramer acetate (Copaxone), IFN-β1a (Avonex and Rebif) and IFN-β1b (Betaxone). Betaseron and Extavia), and second-line approved therapies are mitoxantrone (Novantrone) and natalizumab (Tesabri ( Tysabri)). Recently, fingolomid, terflunomide, and dimethyl fumarate have each been approved by the...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K39/00A61K38/00C07K16/00
CPCC07K16/2842A61K2039/505A61P25/02C07K2317/76A61K38/215A61K31/137A61K2300/00C07K16/2839A61K39/39541
Inventor 巴哈雷·阿贾米劳伦斯·斯坦曼
Owner THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIV
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