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Method for the treatment of pompe disease using 1-deoxynojirimycin and derivatives

A technology of deoxynojirimycin and its derivatives, which can be used in gene therapy, pharmaceutical formulations, genetic material components, etc., and can solve problems such as side effects

Inactive Publication Date: 2009-01-28
AMICUS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This approach is also limited because glycolipids are required for biological function and excessive deprivation can cause side effects

Method used

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  • Method for the treatment of pompe disease using 1-deoxynojirimycin and derivatives
  • Method for the treatment of pompe disease using 1-deoxynojirimycin and derivatives
  • Method for the treatment of pompe disease using 1-deoxynojirimycin and derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0240] Example 1: Synthesis of DNJ and derivatives

[0241] Tetra-O-benzyl-1-deoxynojirimycin [General imino sugar preparation method-1]

[0242]

[0243] DMSO (4.4ml, 0.124mol) in anhydrous CH 2 Cl 2 The solution (75 mL) was placed under an argon atmosphere and cooled to -78 °C. Keeping the temperature at -78 °C, slowly add trifluoroacetic anhydride (6.1 ml, 0.088 mol) in anhydrous CH 2 Cl 2 solution (50 mL). After the addition was complete, the reaction was stirred for an additional 30 minutes and 2,3,4,6-tetra-O-benzylsorbitol (5.4 g, 10 mmol) was added dropwise in CH 2 Cl 2 solution. The reaction was stirred at -78 °C for 90 minutes, then triethylamine (11.2 ml, 0.08 mol) in CH 2 Cl 2 (50 mL) solution to quench the reaction. The reaction was warmed to 0 °C, then concentrated using a rotovap. Dilute the residue with MeOH (75 mL), add 2M NH 3 MeOH (10.0ml, 20.0mmol) solution, followed by formic acid (0.77mL, 20.0mmol), Molecular sieve, add NaCNBH at the en...

Embodiment 2

[0325] Example 2: Increasing Gaa with DNJ and DNJ derivatives

[0326] Experiments described below demonstrate that DNJ and the DNJ derivative N-butyl-DNJ, a known inhibitor of enzymes involved in glycolipid synthesis, can also bind Gaa and increase the activity of mutant Gaa without inhibiting glycolipid synthesis.

[0327] method

[0328] Cell culture and seeding: Cell lines of PM11 (P545L), PM8 and PM12 (both cleavage defects), fibroblasts were used for enhancement experiments. These cells were fibroblasts isolated from patients with Pompe disease. Seed cells at approximately 5000 cells per well in 180 μL medium in sterile black clear bottom 96-well Costar plates and store in 5% CO 2 , Incubate at 37°C for about 3-6 hours. The medium consisted of DMEM containing 10% FBS and 1% penicillin / streptomycin.

[0329] Drug Treatment All test compounds were dissolved in 1:1 DMSO:H at a stock concentration of 100 mM 2 O middle. Perform serial dilutions of cells with another s...

Embodiment 3

[0352] Example 3: In Vivo Gaa Activity Treated with DNJ and DNJ Derivatives

[0353] Drug Administration This example provides information on the effects of DNJ derivatives in mice. Mice were administered DNJ derivative test compound at 0, 1 mg / kg / day, 10 mg / kg / day and 100 mg / kg / day; organs and plasma were collected 2 and 4 weeks after the start of the study. Twenty male C57BL6 (25 g) mice per group were used. Medications are provided in drinking water, so water consumption is monitored daily.

[0354] In the control group (0 mg / kg / day), mice were dosed daily in drinking water (no drug) and divided into two groups. Ten animals were sacrificed two weeks after treatment, blood was collected from the descending aorta or great vein, tissue harvested and necropsy performed. The remaining 10 animals were sacrificed 4 weeks after treatment and subjected to the same evaluation.

[0355] In the first test group, 20 mice were dosed daily with a target of 1 mg / kg-day in the drinkin...

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Abstract

The present invention provides a method for increasing the activity of a mutant or wild-type a-glucosidase enzyme in vitro and in vivo by contacting the enzyme with a specific pharmacological chaperone which is a derivative of 1- deoxynojirimycin. The invention also provides a method for the treatment of Pompe disease by administration of chaperone small molecule compound which is a derivative of 1-deoxynojirimycin. The 1-deoxynojirimycin derivative is substituted at the N or Cl position. Combination therapy with replacement a-glucosidase gene or enzyme is also provided.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. § 119 based on provisional application serial numbers 60 / 682,241, filed May 17, 2005, and 60 / 729,329, filed October 21, 2005, the entire contents of which are incorporated herein Reference. field of invention [0003] The present invention provides a method for enhancing the activity of α-glucosidase and a method for treating Pompedisease, comprising administering to an individual an effective amount of 1-deoxynojirimycin (1-DNJ) and a derivative of 1-DNJ substances, including, for example, N-butyl-1-deoxynojirimycin (NB-DNJ). These compounds were unexpectedly shown to enhance the activity of acid alpha-glucosidase responsible for the pathology of Pompe disease. Background of the invention [0004] Pompe disease [0005] Pompe disease is one of several lysosomal storage diseases. Lysosomal storage diseases are a group of autosomal recessive diseases caused by the ac...

Claims

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Application Information

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IPC IPC(8): A61K48/00
Inventor B·穆格拉格G·李X·朱R·博伊德K·舍斯
Owner AMICUS THERAPEUTICS INC
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