Prevention or treatment of pain associated with peripheral nerve disorders or diseases accompanied by peripheral nerve disorders or stellate cell disorders.
Patent Information
- Authority / Receiving Office
- TW · TW
- Patent Type
- Patents
- Current Assignee / Owner
- TANABE PHARMACEUTICAL CO LTD
- Filing Date
- 2019-07-10
- Publication Date
- 2026-08-01
AI Technical Summary
Current treatments for peripheral nerve disorders and associated pain symptoms, such as diabetic neuropathy, are ineffective, and there is a lack of understanding of the role of RGMa in these conditions, hindering effective therapeutic interventions.
Development of RGMa inhibitory substances, particularly anti-RGMa neutralizing antibodies, to inhibit RGMa activity and improve peripheral nerve function and alleviate pain symptoms by targeting RGMa in peripheral nerve disorders and astrocyte dysfunction.
The use of RGMa inhibitors effectively improves nerve conduction velocity and reduces pain symptoms in models of diabetic neuropathy, suggesting a novel therapeutic approach for peripheral nerve disorders and astrocyte-related pain.
Smart Images
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Abstract
Description
[Technical Field] This invention relates to a preventive or therapeutic agent for pain in peripheral nerve disorders characterized by inhibition of RGMa activity or diseases accompanied by observed peripheral nerve disorders or stellate cell disorders, and to a preventive or therapeutic method using the same. [Previous Technology] Astrocytes are glial cells found in the central nervous system. They possess various functions, including (1) supporting the network of neurons on their structural surfaces, (2) regulating the conditions around the astrocytes through substance transport, (3) performing a single synaptic function among the three cell types (presynapses, postsynapses, and glial cells) through close relationships, (4) regulating extracellular ion concentration, (5) buffering energy, and (6) enhancing myelination activity of oligodendrocytes. The functions of astrocytes, as described above, are noteworthy in various brain diseases, particularly their association with neurodegenerative diseases such as Alzheimer's, Parkinson's, and cognitive impairment caused by the decline in astrocyte function with aging, as well as cerebrovascular disorders and mental illnesses (Non-Patent Literature 1-3). Peripheral nerve disorders are pathological conditions in which the normal conduction of peripheral nerves is impaired. The types of nerves impaired in peripheral nerve disorders include motor nerves, sensory nerves, and autonomic nerves. Peripheral neuropathy is clinically classified into mononeuropathy (mononeurosis; a single nerve disorder), polymononeuropathy (multiple mononeuropathy; disorder of two or more nerves in different areas), or polyneuropathy (polyneuropathy; widespread nerve disorders occurring symmetrically on both sides). Pathologically, it is classified into axonal disorders where the axon is invaded at the center, or myelin disorders due to demyelination and loss of myelin sheath. Peripheral neuropathy can impair motor, sensory, and autonomic nerves. The results are characterized by symptoms such as pain, sensory abnormalities, numbness, tingling, decreased muscle strength, abnormal sweating, or urinary disorders, which worsen over time. The main causes of peripheral neuropathy include physical factors such as deformities leading to injury, compression, circulatory disorders, genetic factors, and metabolic abnormalities. Diabetic neuropathy includes both polyneuropathy and mononeuropathy; polyneuropathy includes disorders of the sensory, motor, and autonomic nerves of the peripheral nervous system. Methyl vitamin B12 (methylcobalamin) (Non-Patent Literature 4) is used clinically as a treatment for peripheral nerve disorders, but clinically effective cases are extremely rare. Furthermore, motor paralysis accompanying nerve disorders profoundly impacts daily life, but effective treatment methods have not yet been established. RGM (repulsive guidance molecule) was initially identified as a membrane protein that guides axons in the visual system (see Non-Patent Literature 5). The RGM family includes three members: RGMa, RGMb, and RGMc (Non-Patent Literature 6). It is known that at least RGMa and RGMb function through the same signal transduction mechanism (see Non-Patent Literature 7). RGMc plays an important role in iron metabolism. Subsequent studies have shown that RGM has functions such as axon guidance and lamina formation in Xenopus and chicken embryos, as well as the control of neural tube closure in mouse embryos (see Non-Patent Literature 8). Patent Literature 1 discloses an axon regeneration promoter containing an anti-RGM neutralizing antibody as an active ingredient. Besides its developmental functions, RGMa re-emerges after central nervous system injury in adults and rats. Furthermore, RGMa inhibition in rats leads to increased axonal growth following spinal cord injury, promoting functional recovery (see Non-Patent Literature 9). Therefore, RGMa is considered an inhibitor of axonal regeneration after central nervous system injury. Specific antibodies that neutralize RGMa are described in Patent Literature 2 (e.g., 5F9, 8D1), Patent Literature 3 (e.g., AE12-1, AE12-1Y), and Patent Literature 4 (e.g., r116A3, r70E4, r116A3C, rH116A3). Additionally, anti-RGMa antibodies are known to be effective against neuromyelitis optica (see Non-Patent Literature 10). Thus, the role of RGMa in central nervous system injury has been clarified, but its association with peripheral nerve disorders or pain symptoms associated with diseases exhibiting peripheral nerve disorders or stellate cell disorders has not yet been identified. [Prior Art Documents] [Patent Documents] [Patent Document 1] International Publication WO2005 / 087268 [Patent Document 2] International Publication WO2009 / 106356 [Patent Document 3] International Publication WO2013 / 112922 [Patent Document 4] International Publication WO2016 / 175236 [Non-Patent Documents] [Non-Patent Literature 1] Dallerac G et al., Prog Neurobiol. 144: 48-67 (2016) [Non-Patent Literature 2] Gerkau NJ et al., J Neurosci Res. 2017 Feb 2. [Non-Patent Literature 3] Alam Q et al., Curr Pharm Des. 22: 541-8 (2016) [Non-Patent Literature 4] Yamazaki et al. Neurosci Lett, 170: 195-197. (1994) [Non-Patent Literature 5] Stahl, B., Muller, B., von Boxberg, Y., Cox, EC & Bonhoeffer, F. Biochemical characterization of a putative axonal guidance molecule of the chick visual system. Neuron 5, 735-743 (1990) [Non-Patent Literature 6] Mueller et al., Philos. Trans. R. Soc. Lond. B Biol. Sci., 361:1513‐29, 2006 [Non-Patent Literature 7] Liu, X., Hashimoto, M., Horii, H., Yamaguchi, A., Naito, K. and Yamashita, T. Repulsive guidance molecule b inhibits neurite growth and is increased after spinal cord injury. Biochem. Biophys. Res. Commun. 382, 795-800 (2009) [Non-Patent Literature 8] Yamashita, T., Mueller, BK & Hata, K. Neogenin and repulsive guidance molecule signaling in the central nervous system. Curr. Opin. Neurobiol.17, 29-34 (2007) [Non-Patent Literature 9] Hata, K. et al.RGMa inhibition promotes axonal growth and recovery after spinal cord injury. J. Cell Biol. 173, 47-58 (2006) [Non-patent document 10] Harada K. et al., Inhibition of RGMa alleviates symptoms in a rat model of neuromyelitis optica. Scientific Reports 8: 34 1-9 (2018). [Summary of the Invention] [The problem that the invention aims to solve] The purpose of this invention is to provide novel methods for the prevention or treatment of pain symptoms associated with peripheral nerve disorders or diseases accompanied by observed peripheral nerve disorders or stellate cell disorders. [Means for solving the problem] The inventors conducted in-depth research to solve the aforementioned problems. As a result, they discovered an RGMa inhibitor that can serve as a preventative or therapeutic agent for peripheral nerve disorders. Furthermore, they discovered that the RGMa inhibitor not only addresses peripheral nerve disorders but also shows effectiveness in relieving pain symptoms by improving stellate cell dysfunction or reduced function. Therefore, it can serve as a preventative or therapeutic agent for pain symptoms associated with diseases accompanied by observed peripheral nerve or stellate cell dysfunction, thus completing this invention. In other words, this invention relates to the following inventions. 1. A preventive or therapeutic agent for peripheral nerve disorders, comprising an RGM inhibitor. 2. The preventive or therapeutic agent of claim 1, wherein the RGM inhibitor is an RGMa inhibitor. 3. The preventive or therapeutic agent of claim 2, wherein the RGMa inhibitor is an anti-RGMa neutralizing antibody or a fragment thereof. 4. The preventive or therapeutic agent of claim 3, wherein the anti-RGMa neutralizing antibody is a humanized antibody. 5. The preventive or therapeutic agent of claim 3 or 4, wherein the anti-RGMa neutralizing antibody is an antibody that recognizes an amino acid sequence selected from sequence numbers 16, 36, 37, 38, and 39. 6. The preventive or therapeutic agent of any of items 3 to 5, wherein the anti-RGMa neutralizing antibody is an antibody selected from (a1) to (l1) below: (a1) an anti-RGMa neutralizing antibody containing a light chain variable region comprising LCDR1 containing the amino acid sequence described in sequence number 5, LCDR2 containing the amino acid sequence described in sequence number 6, and LCDR3 containing the amino acid sequence described in sequence number 7, and a heavy chain variable region comprising HCDR1 containing the amino acid sequence described in sequence number 8, HCDR2 containing the amino acid sequence described in sequence number 9, and HCDR3 containing the amino acid sequence described in sequence number 10. (b1) An anti-RGMa neutralizing antibody comprising a light chain variable region containing an LCDR1 containing the amino acid sequence described in sequence number 11, an LCDR2 containing the amino acid sequence described in sequence number 12, and an LCDR3 containing the amino acid sequence described in sequence number 13, and a heavy chain variable region containing an HCDR1 containing the amino acid sequence described in sequence number 14, an HCDR2 containing the amino acid sequence described in sequence number 15, and an HCDR3 containing SFG in the amino acid sequence; (c1) An anti-RGMa neutralizing antibody comprising a light chain variable region containing an LCDR1 containing the amino acid sequence described in sequence number 17, an LCDR2 containing the amino acid sequence described in sequence number 18, and an LCDR3 containing the amino acid sequence described in sequence number 19, and a heavy chain variable region containing an HCDR1 containing the amino acid sequence described in sequence number 20, an HCDR2 containing the amino acid sequence described in sequence number 21, and an HCDR3 containing the amino acid sequence described in sequence number 22. (d1) includes a light chain variable region comprising LCDR1 containing the amino acid sequence described in sequence number 23, LCDR2 containing the amino acid sequence described in sequence number 24, and LCDR3 containing the amino acid sequence described in sequence number 25.And an anti-RGMa neutralizing antibody containing a heavy chain variable region comprising HCDR1 containing the amino acid sequence described in sequence number 26, HCDR2 containing the amino acid sequence described in sequence number 27, and HCDR3 containing the amino acid sequence described in sequence number 28; (e1) an anti-RGMa neutralizing antibody containing a light chain variable region comprising LCDR1 containing the amino acid sequence described in sequence number 29, LCDR2 containing the amino acid sequence described in sequence number 30, and LCDR3 containing the amino acid sequence described in sequence number 31, and an anti-RGMa neutralizing antibody containing a heavy chain variable region comprising HCDR1 containing the amino acid sequence described in sequence number 32, HCDR2 containing the amino acid sequence described in sequence number 33, and HCDR3 containing the amino acid sequence described in sequence number 34. (f1) An anti-RGMa neutralizing antibody comprising a light chain variable region containing an LCDR1 containing the amino acid sequence described in sequence number 29, an LCDR2 containing the amino acid sequence described in sequence number 30, and an LCDR3 containing the amino acid sequence described in sequence number 35, and a heavy chain variable region containing an HCDR1 containing the amino acid sequence described in sequence number 32, an HCDR2 containing the amino acid sequence described in sequence number 33, and an HCDR3 containing the amino acid sequence described in sequence number 34; (g1) An anti-RGMa neutralizing antibody comprising a light chain variable region containing an LCDR1 containing the amino acid sequence described in sequence number 29, an LCDR2 containing the amino acid sequence described in sequence number 30, and an LCDR3 containing the amino acid sequence described in sequence number 40, and a heavy chain variable region containing an HCDR1 containing the amino acid sequence described in sequence number 32, an HCDR2 containing the amino acid sequence described in sequence number 33, and an HCDR3 containing the amino acid sequence described in sequence number 34. (h1) An anti-RGMa neutralizing antibody comprising a light chain variable region containing an LCDR1 containing the amino acid sequence described in sequence number 29, an LCDR2 containing the amino acid sequence described in sequence number 30, and an LCDR3 containing the amino acid sequence described in sequence number 41, and a heavy chain variable region containing an HCDR1 containing the amino acid sequence described in sequence number 32, an HCDR2 containing the amino acid sequence described in sequence number 33, and an HCDR3 containing the amino acid sequence described in sequence number 34; (i1) An anti-RGMa neutralizing antibody comprising a light chain variable region containing an LCDR1 containing the amino acid sequence described in sequence number 29, an LCDR2 containing the amino acid sequence described in sequence number 30, and an LCDR3 containing the amino acid sequence described in sequence number 42.And an anti-RGMa neutralizing antibody containing the heavy chain variable region of HCDR1 containing the amino acid sequence described in sequence number 32, HCDR2 containing the amino acid sequence described in sequence number 33, and HCDR3 containing the amino acid sequence described in sequence number 34; (j1) an anti-RGMa neutralizing antibody containing the light chain variable region of LCDR1 containing the amino acid sequence described in sequence number 29, LCDR2 containing the amino acid sequence described in sequence number 30, and LCDR3 containing the amino acid sequence described in sequence number 43, and an anti-RGMa neutralizing antibody containing the heavy chain variable region of HCDR1 containing the amino acid sequence described in sequence number 32, HCDR2 containing the amino acid sequence described in sequence number 33, and HCDR3 containing the amino acid sequence described in sequence number 34. (k1) an anti-RGMa neutralizing antibody comprising a light chain variable region comprising LCDR1 containing the amino acid sequence described in sequence number 29, LCDR2 containing the amino acid sequence described in sequence number 30, and LCDR3 containing the amino acid sequence described in sequence number 44, and a heavy chain variable region comprising HCDR1 containing the amino acid sequence described in sequence number 32, HCDR2 containing the amino acid sequence described in sequence number 33, and HCDR3 containing the amino acid sequence described in sequence number 34, and (l1) an anti-RGMa neutralizing antibody comprising a light chain variable region comprising LCDR1 containing the amino acid sequence described in sequence number 29, LCDR2 containing the amino acid sequence described in sequence number 30, and LCDR3 containing the amino acid sequence described in sequence number 45, and a heavy chain variable region comprising HCDR1 containing the amino acid sequence described in sequence number 32, HCDR2 containing the amino acid sequence described in sequence number 33, and HCDR3 containing the amino acid sequence described in sequence number 34. 7. For any of the preventive or therapeutic agents in items 1-6, the peripheral neuropathy is selected from diabetic neuropathy, snare neuropathy (carpal tunnel syndrome, ulnar nerve palsy at the elbow, peroneal nerve palsy, or tarsal tunnel syndrome), familial amyloid polyneuropathy, toxic neuropathy, carcinomatous neuropathy, immune-mediated neuropathy (Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP)), neuropathy associated with collagen diseases, Crow-Fukase syndrome (POEMS syndrome), hereditary neuropathy (Charcor-Marie-Tooth disease), postherpetic neuralgia, peripheral neuropathy caused by AIDS or Lyme disease, uremia, multifocal motor neuropathy, and vasculitic neuropathy. 8. For any of the preventive or therapeutic agents in items 1-6, the peripheral neuropathy is diabetic neuropathy. 9. As in item 8, preventive or therapeutic agents, including diabetic neuropathy, specifically painful diabetic neuropathy.And / or asymptomatic diabetic neuropathy. 10. The preventive or therapeutic agent of any of items 1 to 6, which is used for the prevention or treatment of pain symptoms caused by diseases observed to be peripheral nerve disorders or stellate cell disorders. 11. The preventive or therapeutic agents of item 10, wherein the diseases in which peripheral nerve disorders or stellate cell disorders are observed, are selected from diabetic neuropathy, snare neuropathy (carpal tunnel syndrome, ulnar nerve disorder of the elbow, peroneal nerve palsy or tarsal tunnel syndrome), familial amyloid polyneuropathy, toxic neuropathy, carcinomatous neuropathy, immune-mediated neuropathy (Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP)), neuropathy associated with collagen disease, Crow-Fukase syndrome (POEMS syndrome), hereditary neuropathy (Charcor-Marie-Tooth disease), postherpetic neuralgia, peripheral nerve disorders caused by AIDS or Lyme disease, uremia, multifocal motor neuropathy, vasculitic neuropathy, neuromyelitis optica, and Alexander's disease. 12. The preventive or therapeutic agent of claim 11, wherein the observed peripheral nerve disorder or stellate cell disorder is diabetic neuropathy or neuromyelitis optica. 13. The preventive or therapeutic agent of claim 11, wherein the observed peripheral nerve disorder or stellate cell disorder is diabetic neuropathy. 14. The preventive or therapeutic agent of claim 11, wherein the observed peripheral nerve disorder or stellate cell disorder is neuromyelitis optica. 15. A method for preventing or treating peripheral nerve disorder comprising administering an effective amount of an RGMa inhibitor to a mammal requiring treatment. 16. The method of claim 15, wherein the peripheral nerve disorder is diabetic neuropathy. [Effects of the Invention] According to the present invention, preventive or therapeutic agents for peripheral nerve disorders can be provided. Furthermore, the present invention can provide preventive or therapeutic agents for pain symptoms accompanying diseases observed to have peripheral nerve disorders or stellate cell disorders.
Implementation Method
Claims
1. The use of an anti-RGMa neutralizing antibody or a fragment thereof for the manufacture of a preventive or therapeutic agent for peripheral nerve disorders, wherein, Peripheral neuropathy is diabetic neuropathy, and the aforementioned anti-RGMa neutralizing antibody is as follows (a1): (a1) an anti-RGMa neutralizing antibody containing a light chain variable region containing an amino acid sequence of sequence number 5, an amino acid sequence of sequence number 6, and an amino acid sequence of sequence number 7, and a heavy chain variable region containing an amino acid sequence of sequence number 8, an amino acid sequence of sequence number 9, and an amino acid sequence of sequence number 10.
2. As requested in item 1, wherein the anti-RGMa neutralizing antibody is a humanized antibody.
3. As requested in item 1, wherein the anti-RGMa neutralizing antibody is an antibody that recognizes an amino acid sequence selected from sequence number 16, sequence number 36, sequence number 37, sequence number 38 and sequence number 39.
4. As used in claim 1, wherein the diabetic neuropathy is painful diabetic neuropathy and / or asymptomatic diabetic neuropathy.
5. The use of an anti-RGMa neutralizing antibody or a fragment thereof, which is used in the manufacture of a preventive or therapeutic agent for pain symptoms caused by diseases observed to be peripheral nerve disorders or stellate cell disorders, wherein, The observed peripheral nerve disorder or stellate cell disorder is diabetic neuropathy, and the aforementioned anti-RGMa neutralizing antibody is as follows (a1): (a1) an anti-RGMa neutralizing antibody containing a light chain variable region containing an amino acid sequence of sequence number 5, an amino acid sequence of sequence number 6, and an amino acid sequence of sequence number 7, and a heavy chain variable region containing an amino acid sequence of sequence number 8, an amino acid sequence of sequence number 9, and an amino acid sequence of sequence number 10.
6. As requested in item 5, wherein the anti-RGMa neutralizing antibody is a humanized antibody.
7. As requested in item 5, wherein the anti-RGMa neutralizing antibody is an antibody that recognizes an amino acid sequence selected from sequence number 16, sequence number 36, sequence number 37, sequence number 38 and sequence number 39.