Application of 2-hydroxypropyl-β-cyclodextrin in preparation of medicine for treating X-linked adrenoleukodystrophy

A cyclodextrin, adrenal brain technology, applied in the field of biomedicine, can solve the problems of staying, infeasible, unable to prevent demyelination, etc., and achieve the effect of reducing the level of VLCFA and alleviating abnormal behavioral symptoms

Active Publication Date: 2017-12-08
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When adrenal insufficiency occurs, hormone replacement therapy can be used. Giving steroid hormones can significantly improve the patient's endocrine state, but cannot improve the symptoms of the nervous system; a low-fat diet combined with Lorenzo's oil (trierucicin: triolein = 4:1) may have a certain effect on reducing the level of VLCFA in plasma in some patients, but it cannot prevent the demyelination of the brain; gene therapy has great prospects but is not feasible in the near future; hematopoietic stem cell transplantation can effectively treat patients with brain type in the early stage of the disease, But it is not suitable for patients with brain type in the rapidly progressive stage of the disease; the use and efficacy of drug-induced gene therapy such as lovastatin are still at the experimental level
[0004] Lorenzo’s oil, which is currently the most widely used treatment for X-ALD, can reduce the level of VLCFA in the plasma of some patients, but it cannot improve the brain lesions and behavioral abnormalities caused by X-ALD
Another experimental small molecule, 4-PBA, was well tolerated by patients but failed to reduce VLCFA levels in the body

Method used

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  • Application of 2-hydroxypropyl-β-cyclodextrin in preparation of medicine for treating X-linked adrenoleukodystrophy
  • Application of 2-hydroxypropyl-β-cyclodextrin in preparation of medicine for treating X-linked adrenoleukodystrophy
  • Application of 2-hydroxypropyl-β-cyclodextrin in preparation of medicine for treating X-linked adrenoleukodystrophy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1 HPCD injection X-ALD mouse procedure

[0022] The materials used in this example: 2-hydroxypropyl-β-cyclodextrin (2-hydroxypropyl-β-cyclodextrin) HPCD was purchased from Cyclodextrin Technologies Development, Inc., and ABCD1 knockout mice were purchased from Jackson Laboratory.

[0023] according to figure 1 The procedure shown is for wild-type (WT) and X-ALD model mice (ABCD1 knockout mice, ABCD1 - / - Mice) were injected with HPCD on the back of the neck. The injection dose was 4000mg HPCD per kg of mouse body weight. The details were as follows: 20% HPCD (W / V) was prepared with 0.9% saline, and 6-month to 7-month-old mice were injected 4 weekly 20% HPCD, the control group was injected with the same volume of normal saline. Filipin staining of cells, Filipin staining of adrenal and cerebellar tissue sections, and measurement of plasma total cholesterol and very long-chain fatty acids were performed at 7 months of age; 7 months to 12 months of age The mice were inje...

Embodiment 2

[0024] Example 2 HPCD relieves cholesterol accumulation in X-ALD mouse cells

[0025] Material used in this example: Filipin was purchased from Sigma.

[0026] In order to test whether HPCD can improve the symptoms of cholesterol accumulation at the cell level of X-ALD mice, the 7-month-old WT and ABCD1 injected with saline and HPCD in Example 1 were taken. - / - Mice, separated and cultured their tail tip fibroblasts for observation by Filipin staining.

[0027] Filipin staining: the isolated and cultured tail tip fibroblasts are fixed with 4% paraformaldehyde for 30 min at room temperature; washed twice with PBS; dilute the ethanol-dissolved Filipin mother solution (5 mg / mL) with PBS containing 10% fetal bovine serum (FBS) to The final concentration is 50μg / mL, and incubate at room temperature for 30min in the dark; wash with PBS three times and wash with deionized water twice; mount the slides, dry overnight, observe with laser confocal microscope, and store at -20℃.

[0028] Filipin...

Embodiment 3

[0029] Example 3 HPCD relieves the accumulation of cholesterol in the tissues of X-ALD mice, reduces plasma total cholesterol and very long chain fatty acids (VLCFA)

[0030] To test whether HPCD can improve the symptoms of cholesterol accumulation in the tissues of X-ALD mice, reduce plasma total cholesterol and very long chain fatty acids (VLCFA). Take 7-month-old WT and ABCD1 injected with saline and HPCD in Example 1. - / - In mice, the adrenal glands and cerebellum were separated for frozen section and Filipin staining, and the plasma total cholesterol and very long-chain fatty acids were measured.

[0031] (1) Tissue section staining: cut the thoracic cavity of the mouse after anesthesia, insert a 20mL syringe connected to the scalp needle through the left ventricle, and cut a small mouth at the right atrial appendage with scissors, push in 20mL saline, and quickly change to 20mL after pushing. 4% paraformaldehyde; take out the adrenal glands and cerebellum of the required tiss...

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Abstract

The invention discloses the application of 2-hydroxypropyl-β-cyclodextrin (HPCD) in the preparation of medicines for treating X-linked adrenoleukodystrophy (X-ALD), and belongs to the field of biomedicine. The present invention injects 2-hydroxypropyl-β-cyclodextrin into wild-type and X-ALD model mice (ABCD1 gene knockout mice), and performs cell, adrenal gland and cerebellum tissue sections on cells injected with HPCD mice Filipin staining was performed to measure plasma total cholesterol, very long-chain fatty acids, body weight, and behavioral tests. It was found that HPCD can reduce the cholesterol levels of plasma, cerebellum, and adrenal glands to within the normal range, and reduce the level of VLCFA. Alleviated behavioral abnormalities caused by neurodegeneration in X‑ALD mice. Based on this result, it is shown that HPCD can treat X-ALD, and it can be used to prepare a medicine for treating X-ALD.

Description

Technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to the application of 2-hydroxypropyl-β-cyclodextrin in the preparation of medicines for the treatment of X-linked adrenal degeneration. Background technique [0002] X-linked adrenal degeneration (X-ALD) is an X-linked recessive inherited lipid metabolism disease. It is currently believed that the oxidation of very long-chain fatty acids (VLCFA), mainly C23~C30 fatty acids, especially C26, occurs due to peroxisomes in cells, so that VLCFA is abundant in blood, white matter, adrenal cortex and other organs and tissues. Aggregate, causing central nervous system demyelination and adrenal cortex atrophy or dysplasia. Approximately 0.5-1 people per 100,000 people suffer from the disease, 95% of whom are males and 5% are female heterozygotes. X-ALD pathogenic gene ABCD1 (Sarde et al., 1994) encodes the peroxisome membrane protein ALDP (adrenoleukodystrophy protein), which contains 745 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/724A61P3/06
Inventor 宋保亮储贝贝廖雅成
Owner WUHAN UNIV
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