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Application of 2-hydroxypropyl-beta-cyclodextrin to the preparation of drug for treatment of X-linked adrenoleukodystrophy

A cyclodextrin, adrenal brain technology, applied in the field of biomedicine, can solve the problems of staying, infeasible, unable to improve X-ALD brain lesions and behavioral abnormalities, so as to reduce the level of VLCFA and alleviate the symptoms of behavioral abnormalities. Effect

Active Publication Date: 2015-08-26
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-beta-cyclodextrin to the preparation of drug for treatment of X-linked adrenoleukodystrophy
  • Application of 2-hydroxypropyl-beta-cyclodextrin to the preparation of drug for treatment of X-linked adrenoleukodystrophy
  • Application of 2-hydroxypropyl-beta-cyclodextrin to the preparation of drug for treatment of X-linked adrenoleukodystrophy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Embodiment 1 HPCD injects X-ALD mouse procedure

[0022] 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 indicated procedures are effective for wild-type (WT) and X-ALD model mice (ABCD1 knockout mice, ABCD1 - / - Mice) were injected with HPCD at the back of the neck, and the injection dose was 4000 mg HPCD per kg of mouse body weight, specifically as follows: prepare 20% HPCD (W / V) with 0.9% normal saline, and inject 4 weeks of mice from 6 months to 7 months of age 20% HPCD once, the control group was injected with the same volume of normal saline, and Filipin staining of cells, Filipin staining of adrenal gland and cerebellar tissue sections, and measurement of plasma total cholesterol and very long-chain fatty acids were performed at the age of 7 months; ...

Embodiment 2

[0024] Example 2 HPCD alleviates intracellular cholesterol accumulation in X-ALD mice

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

[0026] In order to detect whether HPCD can improve the symptoms of cholesterol accumulation at the cellular level of X-ALD mice, the 7-month-old WT, ABCD1 - / - In mice, the tail tip fibroblasts were isolated and cultured for Filipin staining observation.

[0027] Filipin staining: the isolated and cultured tail tip fibroblasts were fixed with 4% paraformaldehyde at room temperature for 30 min; washed twice with PBS; diluted ethanol-dissolved Filipin mother solution (5 mg / mL) with PBS containing 10% fetal bovine serum (FBS) to The final concentration was 50 μg / mL, and incubated at room temperature in the dark for 30 minutes; washed three times with PBS and twice with deionized water; sealed, dried overnight, observed under a laser confocal microscope, and stored at -20°C.

[0028] Filipin staining results are as foll...

Embodiment 3

[0029] Example 3 HPCD alleviates tissue cholesterol accumulation in 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 at the tissue level in X-ALD mice, and reduce plasma total cholesterol and very long-chain fatty acids (VLCFA). Get the 7-month-old WT, ABCD1 injected with normal saline and HPCD respectively in Example 1 - / - In mice, the adrenal gland and cerebellum were isolated for frozen section and Filipin staining, and plasma total cholesterol and very long-chain fatty acids were measured.

[0031](1) Staining of tissue sections: cut open the thorax of the mouse after anesthesia, insert a 20mL syringe connected to the scalp needle through the left ventricle, cut a small mouth at the right atrial appendage with scissors, push in 20mL of normal saline, and quickly change to 20mL after pushing 4% paraformaldehyde; take out the adrenal gland and cerebellum, a...

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Abstract

The present invention discloses application of a 2-hydroxypropyl-beta-cyclodextrin (HPCD) to the preparation of the drug for the treatment of X-linked adrenoleukodystrophy (X-ALD), and belongs to the biomedical field. The invention is as below: injecting 2-hydroxypropyl-beta-cyclodextrin into the wild mice and X-ALD model mice (ABCD1 knockout), conducting Filipin staining on the cell, adrenal gland and cerebellum tissue slices of the mice injected with HPCD; measuring the plasma total cholesterol, very long chain fatty acids and weight, and conducting behavioral tests. The results show that HPCD can make cholesterol levels if plasma, cerebellum and adrenal drop into the normal range, also reduce the VLCFA levels, and mitigate the behavior abnormalities caused by neurodegeneration of X-ALD mice. The results show that HPCD can treat X-ALD and can be applied to the drug for treatment of 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 treating X-linked adrenoleukodystrophy. Background technique [0002] X-linked adrenoleukodystrophy (X-ALD) is an X-linked recessive genetic disorder of lipid metabolism. At present, it is believed that because peroxisomes in the cells are hindered in the oxidation of very long-chain fatty acids (VLCFA), mainly C23-C30 fatty acids, especially C26, resulting in a large amount of VLCFA in blood, brain white matter, adrenal cortex and other organs and tissues. Aggregates, causing demyelination of the central nervous system and atrophy or dysplasia of the adrenal cortex. About 0.5-1 person per 100,000 people has the disease, of which 95% are males and 5% are heterozygous females. The X-ALD pathogenic gene ABCD1 (Sarde et al., 1994) encodes the peroxisome membrane protein ALDP (adrenoleukodyst...

Claims

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Application Information

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IPC IPC(8): A61K31/724A61P3/06
Inventor 宋保亮储贝贝廖雅成
Owner WUHAN UNIV
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