Method of treating inflammtory disease associated with bone destruction

A technology for inflammatory diseases and bone destruction, applied in the field of inflammatory diseases, can solve problems such as difficult bone and joint destruction, delayed bone destruction, and weakened effect of neutralizing antibodies

Inactive Publication Date: 2006-06-14
DNAVEC RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, a major problem is that it is ultimately difficult to prevent bone and joint destruction
That is to say, although traditional techniques and drugs have the effect of relieving subjective and objective symptoms by inhibiting synovitis, they have poor effects on directly inhibiting bone and joint destruction
The only effect observed using traditional techniques and drugs is a delay in the progression of bone destruction, which is thought to be a result of suppression of inflammation, making it difficult to ultimately avoid bone and joint destruction
Not only that, in the treatment with chimeric neutralizing antibodies, due to the simultaneous production of human anti-neutralizing antibodies, the effect of neutralizing antibodies is weakened, so these therapies must be used in clinical use with immunosuppressants such as methotrexate
In addition, there is a perception that various unintended side effects may occur in non-lesional organs during anti-cytokine therapy targeting inflammatory cytokines, as well as in systemic delivery systems for biological agents

Method used

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  • Method of treating inflammtory disease associated with bone destruction
  • Method of treating inflammtory disease associated with bone destruction
  • Method of treating inflammtory disease associated with bone destruction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] [Example 1] Raf inhibitor affects the formation of cultured osteoclasts

[0065] 1. Isolation and culture of macrophages derived from rat bone marrow

[0066] Macrophages derived from rat bone marrow were isolated and cultured with macrophage colony-stimulating factor (M-CSF). Eight Lewis rats of Charles-River grade (6-week-old, KBT Oriental Co., Ltd., Tosu, Saga) were sacrificed under anesthesia by dislocation of the neck, and the carotid artery was cut off for debleeding. The diaphysis of both femurs and tibias was removed under aseptic conditions, and the culture medium (α-modified essential medium: α-MEM (GIBCO BRL, Rockville, Maryland, USA)) was injected into the bone marrow cavity to collect bone marrow cells. Red blood cells were used 0.727% NH 4 Cl-0.017% Tris-Cl (pH7.2)-phosphate buffered saline (PBS) after washing, wash with 10% fetal bovine serum (FBS) and recombinant human M-CSF (rhM-CSF, 10ng / ml, CHEMICON International , Inc.Temecula, CA) α-MEM will b...

Embodiment 2

[0069] [Example 2] Effect of introducing sFGFR gene on AIA: extracellular blockade of FGF-2

[0070]

[0071] 1. AIA model

[0072] In order to establish the AIA model, rats were subcutaneously injected with 1 mg of dead Mycobacterium tuberculosis (Desiccated: Mycobacterium Butyricum: MBD, Difco, Detroit, MI, USA) dissolved in mineral oil (NACALAI 100 μl suspension in TESQUE, Kyoto).

[0073] 2. Protocol for Extracellular Blockade of FGF2

[0074] Direct gene transfer using a recombinant Sendai virus vector (SeV) was performed to locally express the target gene in inflammation in rats, and then the effect on arthritis was examined. Specifically, the onset of arthritis was first confirmed, and then, 14 days after the administration of the adjuvant, the AIA+sFGFR group (n=40) was administered SeV with a soluble FGF receptor gene (sFGFR, SEQ ID NO: 1) on the foot pad. (SeV-sFGFR), 10 8 pfu / foot; AIA+luciferase control group (n=28) footpad administration of SeV (SeV-lu...

Embodiment 3

[0083] [Example 3] Influence of introducing Spry2 gene on AIA: blocking FGF-2 intracellular signal

[0084]

[0085] 1. AIA model

[0086] A 100 μl suspension of 1 mg of dead Mycobacterium tuberculosis (dried Mycobacterium butyricum: MBD, Difco) dissolved in mineral oil (NACALAI TESQUE) was injected subcutaneously at the base of the tail of the rat.

[0087] 2. Protocol for Intracellular Blockade of FGF2

[0088] Direct gene transfer using a recombinant Sendai virus vector (SeV) was performed to locally express the target gene in inflammation in rats, and then the effect on arthritis was examined. Specifically, the onset of arthritis was first confirmed, and then, 14 days after the administration of the adjuvant, the AIA+Spry2 group (n=33) was administered SeV (SeV- spry2), 10 8 pfu / foot; AIA+luciferase control group (n=33) footpad administration of SeV (SeV-luciferase) with luciferase gene, 10 8 pfu / foot.

[0089] 3. Determination of hindlimb volume

[0090] H...

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PUM

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Abstract

The present invention relates to a method for treating inflammatory diseases accompanied by bone destruction, comprising administering to the diseased site a viral vector containing inhibitory fibroblast growth factor-2 (FGF2)-FGF receptor 1-Ras-Raf-MAP kinase Genes that mediate signaling. The present invention also relates to a therapeutic composition for the treatment of inflammatory diseases accompanied by bone destruction, comprising the above-mentioned carrier. Inhibition of FGF2 signaling by topical administration of viral vectors can simultaneously inhibit both inflammation and bone destruction in inflammatory bone destruction. The invention provides an effective treatment method and a treatment composition specifically for inflammatory diseases such as osteoarthritis which are currently difficult to treat.

Description

technical field [0001] The present invention relates to the treatment of inflammatory diseases associated with bone destruction by modulating the function of fibroblast growth factor-2 (FGF2) and inhibiting its intracellular signaling system. The methods of the invention are particularly useful in the treatment of rheumatoid arthritis (RA). Background technique [0002] Today's world research on RA treatment has developed multiple strategies and disease modifying antirheumatoid drugs (DMARDs). The main techniques of RA treatment (RA treatment strategies) are listed below. These techniques are treatments and strategies using biological agents against RA. [0003] (1) Treatments that regulate tumor necrosis factor (TNF) [0004] These are soluble TNF receptors used in RA therapy (Moreland, L.W. et al., N. Engl. J. Med. 337: 141-147 (1997); Bathon, J. M. et al., N. Engl. J. Med. 343:1586-1593 (2000)) or anti-TNF-α antibody (Maini, R.N.et al., Ann.Rheum.Dis.58:156-160 (1999)...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/17A61K31/7088A61K35/76A61K38/00A61K48/00A61P19/02A61P19/08A61P19/10A61P29/00A61P43/00C07K14/47
CPCA61K31/7088A61K38/00A61P19/02A61P19/08A61P19/10A61P29/00A61P43/00C07K14/4703A61K38/17A61K48/00
Inventor 居石克夫米满吉和山下彰久吉村昭彦长谷川护
Owner DNAVEC RES
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