PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) inhibitor in preparing medicine for treating T-cell medicated inflammatory-immune diseases

An inflammatory immune and inhibitory technology, applied in the field of medicine and biology, can solve the problems that the metabolic disorder of psoriasis patients cannot be effectively improved, and the therapeutic targets for psoriatic skin lesions and associated metabolic abnormalities cannot be found, and the therapeutic effect is remarkable. , Small side effects, small side effects

Inactive Publication Date: 2018-05-25
陈敏
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  • Abstract
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  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In summary, none of the currently marketed drugs can effectively improve the metabolic disorders in patients with psoriasis
S

Method used

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  • PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) inhibitor in preparing medicine for treating T-cell medicated inflammatory-immune diseases
  • PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) inhibitor in preparing medicine for treating T-cell medicated inflammatory-immune diseases
  • PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) inhibitor in preparing medicine for treating T-cell medicated inflammatory-immune diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] PCSK9 knockout significantly alleviates IMQ-induced psoriasis-like inflammatory response in mice

[0047] Main reagents: 5% imiquimod cream (IMQ), PCSK9 primary antibody (abcam company), NF-kB primary antibody (abcam company)

[0048] Experimental animals: C57BL / 6 (B6) mice, 7 males; C57BL / 6-PCSK9- / - mice, 5 males and 5 males. These mice were purchased from The Jackson Laboratory, Maine, USA.

[0049] experimental method:

[0050] (1) After hair removal on the back of two groups of mice with different genotypes, 62.5 mg of 5% imiquimod cream was applied every day for 5 consecutive days.

[0051] (2) Make scores (erythema, scales, thickening of skin lesions and total score) every day before and after application of the drug, and take photos for archiving (the scores are averaged by two researchers).

[0052] (3) On the last day of the experiment, all mice were sacrificed, and back skin tissues (treated area and non-treated area) were collected.

[0053] (4) HE staini...

Embodiment 2

[0060] si-PCSK9 transfection enhances apoptosis and inhibits proliferation of human keratinocytes

[0061] Experimental materials and reagents:

[0062] (1) Human primary keratinocytes (Lifeline Cell Technology, FC-0064);

[0063] (2) DermaLife keratinocyte culture medium (Lifeline Cell Technology, LL-0007), si-PCSK9 (Santa Cruz, sc-45482), Lipofectamine 3000 transfection reagent (ThermalFisher, L-3000001), AnnexinV (BD), PI (BD).

[0064] experimental method:

[0065] (1) Cultivate primary human keratinocytes and plant them in 6-well plates. When the cell density is 60-70%, perform si-RNA (si-Con&si-PCSK9) transfection. After transfection, 24h / 48h / 72h respectively The cell viability of each well was measured by the MTT method, three wells were counted at each time point of the two groups of cells, the average value was taken, and the cell viability curve was drawn;

[0066] (2) Cultivate primary human keratinocytes and plant them in 6-well plates. When the cell density is...

Embodiment 3

[0071] The expression of PCSK9 in skin lesions of patients with psoriasis was significantly higher than that of non-lesional and normal controls

[0072] Experimental materials: skin lesions and non-lesions of 30 cases of psoriasis patients and 30 cases of normal human skin, PCSK9 antibody (abcam company).

[0073] Experimental methods: immunohistochemistry, real-time quantitative-PCR.

[0074] Experimental results: The lesions and non-lesions of the patients were obtained by drilling, and the normal skin was obtained from the excess skin of cosmetic surgery. The results of immunohistochemistry showed that the expression of PCSK9 in the skin lesions of psoriasis patients was significantly higher than that of non-skin lesions and normal controls; PCSK9-positive cells were mainly distributed in the epidermis and the cells near the epidermis in the dermis, and in the cells in the dermal blood vessels. no expression (see Figure 8 ). RNA was extracted after skin homogenization,...

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Abstract

The invention belongs to the technical field of medicine biologics, relates to functions and mechanisms of PCSK9 (Proprotein Convertase Subtilisin/Kexin 9) in treating T-cell medicated inflammatory-immune diseases, application of a PCSK9 inhibitor in preparing a medicine for treating T-cell medicated inflammatory-immune diseases, and in particular relates to application of a PCSK9 small-molecule interference RNA or PCSK9 small-molecule inhibitor in preparing medicines for preparation systems or external skin application in treating psoriasis, atopic dermatitis or urticaria. Psoriasis is adopted as a testing bed for inflammatory-immune disease research, results show that the PCSK9 small-molecule inhibitor or small-molecule interference RNA has treatment effects which are remarkably prior tothose of PCSK9 monoclonal antibodies in treating inflammation such as psoriasis. The PCSK9 small-molecule interference RNA or PCSK9 small-molecule inhibitor can be further developed into novel medicines for treating inflammatory-immune diseases such as psoriasis, and is small in side effect, low in cost and remarkable in treatment effect.

Description

1. Technical field [0001] The invention belongs to the field of medical biotechnology, and specifically relates to the function and mechanism of PCSK9 in T cell-mediated inflammatory immune diseases, and the application of PCSK9 inhibitors in the preparation of drugs for treating T cell mediated inflammatory immune diseases. 2. Background technology [0002] High incidence of inflammatory immune diseases, at least hundreds of millions of patients worldwide, including a variety of refractory diseases, such as psoriasis, eczema (atopic dermatitis), lupus erythematosus, rheumatoid arthritis, dermatomyositis , scleroderma, Crohn's disease, etc., because these diseases can involve multiple organs, resulting in heart, liver, kidney, blood vessel, lung, joint and brain damage, and its mortality rate is second only to malignant tumors. In view of the complex etiology and pathogenesis of this type of disease, it is still impossible to cure it. The commonly used clinical drugs are mai...

Claims

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Application Information

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IPC IPC(8): A61K45/00A61P37/00A61P17/06A61P17/00A61P19/02A61P29/00A61P3/10A61P1/16A61P35/00C12Q1/6883
CPCA61K45/00C12Q1/6883C12Q2600/178
Inventor 陈敏袁荣栾超
Owner 陈敏
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