Method to predict response to pharmacological chaperone treatment of diseases

a technology of pharmacological chaperone and disease, applied in the direction of drugs, instruments, metabolic disorders, etc., can solve the problems of protein stability reduction, protein level of biological activity reduction, and prevent protein folding properly

Inactive Publication Date: 2011-06-23
AMICUS THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0025]In a further embodiment, the invention relates to a method of treating a patient diagnosed with Fabry disease by administering to the patient a therapeutically effective dose of 1-deoxygalactonorigirimycin, or a similar

Problems solved by technology

Certain human diseases result from mutations that cause changes in the amino acid sequence of a protein which reduce its stability and may prevent it from folding properly.
Because of this error, missense mutations often result in proteins that have a reduced level of biological activity.
The retention of misfolded proteins in the ER interrupts their proper trafficking, and the resulting reduced biological activity can lead to impaired cellular function and ultimately to disease.
In addition, the accumulation of misfolded proteins in the ER may lead to various types of stress on cells, which may also contribute to cellular dysfunction and disease.
This results in the pathologic accumulation of substrates of those enzymes, which include lipids, carbohydrates, and polysaccharides.
For most LSDs, there is no available treatment beyond symptomatic management.
This results in the enzyme deficiency in the lysosome, and the pathologic accumulation of substrate.
Because Fabry disease is rare, involves multiple organs, has a wide age range of onset, and is heterogeneous, proper diagnosis is a challenge.
Awareness is low among health care professionals and misdiagnoses are frequent.
This is a concern because the longer a person has Fabry disease, the more damage is likely to occur in the affected organs and tissues and the more serious the person's condition may become.
In females, diagnosis is even more challenging since the enzymatic identification of carrier females is l

Method used

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  • Method to predict response to pharmacological chaperone treatment of diseases
  • Method to predict response to pharmacological chaperone treatment of diseases
  • Method to predict response to pharmacological chaperone treatment of diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Identification of Fabry Disease-Causing Mutations that are Responsive to the Pharmacological Chaperone DGJ

[0138]The present Example provides the in vitro diagnostic assay to determine a Fabry patient's responsiveness to a specific pharmacological chaperone.

Introduction

[0139]Fabry disease is a lysosomal storage disorder caused by mutations in the gene that encodes α-galactosidase A (α-GAL A). Over 600 Fabry mutations have been reported, and about 60% are missense. The iminosugar DGJ is currently being studied in Phase 2 clinical trials as a pharmacological chaperone for the treatment of Fabry disease. Previously, it has been shown that DGJ mediates selective and dose-dependent increases in α-Gal A levels in many Fabry patient-derived lymphoid cell lines. To identify additional DGJ-responsive mutations, GripTite 293 MSR, (Invitrogen Corp., Carlsbad, Calif., U.S.A.) cells were transiently transfected with expression vectors containing all known α-Gal A missense mutations and several in...

example 2

Ex Vivo Method for Evaluating Effects of an SPC on Glucocerebrosidase Activity—Prophetic Example

[0151]Gaucher disease (GD) is caused by a deficiency of lysosomal glucocerebrosidase (GCase). Deficient GCase activity leads to an accumulation of glucosylceramide (GlcCer) and the development of symptoms such as anemia, thrombocytopenia, hepatosplenomegaly, bone necrosis, infarcts and osteoporosis, and in some cases, neuropathic disease. The specific pharmacological chaperone isofagomine tartrate (IFG) selectively binds and stabilizes mutant (N370S / N370S) GCase in the ER and increases its trafficking to the lysosome.

[0152]To evaluate the effects of IFG on different GCase variants, an ex vivo diagnostic assay will be prepared using Cos7 cells in order to ascertain IFG-responsive mutations.

[0153]Using the techniques described in Examples 1 and 4, COS-7 cell lines will be prepared that express missense mutations and several in-frame small deletions and insertions by site-directed mutagenesi...

example 3

In Vivo Effect of an SPC on α-GAL A Activity in Skin, Heart, Kidney and Plasma

[0156]To determine if increased mutant α-Gal A levels translate to increased α-Gal A activity in situ, the effect of DGJ administration on tissue GL-3 levels was investigated in vivo in hR301Q α-Gal A Tg / KO mice.

[0157]Eight-week old male hR301Q α-Gal A Tg / KO mice were treated for 4 weeks with 300 mg / kg DGJ in drinking water either daily or less frequently (4 days ON / 3 days OFF). After dosing, lysates were prepared from skin, heart, kidney, and plasma by homogenizing ˜50 mg tissue in Lysis Buffer (see above). 20 μL lysate were mixed with 50 μL of substrate (as detailed above). Reaction mixtures were incubated at 37° C. for 1 hr. After, 70 μL Stop Solution were added and fluorescence was read on a Victor plate reader as described above. Enzyme activity in the lysates was background subtracted, and normalized for protein concentration. A 4-MU standard curve was run for conversion of fluorescence data to absol...

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Abstract

The present invention provides methods to determine whether a patient with a lysosomal storage disorder will benefit from treatment with a specific pharmacological chaperone. The present invention exemplifies an in vitro method for determining α-galactosidase A responsiveness to a pharmacological chaperone such as 1-deoxygalactonojirimycin in a cell line expressing a mutant from of α-galactosidase A. The invention also provides a method for diagnosing Fabry disease in patients suspected of having Fabry disease.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]The present application is a continuation-in-part of U.S. application Ser. No. 12 / 855,468, filed Aug. 12, 2010, which is a continuation of International Patent Application No. PCT / US09 / 033,963, filed Feb. 12, 2009, which claims the benefit of U.S. Provisional Application No. 61 / 028,141, filed Feb. 12, 2008, U.S. Provisional Application No. 61 / 035,684, filed Mar. 11, 2008, U.S. Provisional Application No. 61 / 093,631, filed Sep. 2, 2008, and U.S. Provisional Application No. 61 / 113,496, filed Nov. 11, 2008, the disclosures of which are herein incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention provides methods to determine whether a patient with a lysosomal storage disorder will benefit from treatment with a specific pharmacological chaperone. The present invention also provides an in vitro method for determining enzyme (e.g., α-galactosidase A, α-glucosidase or glucocerebrosidase) responsiveness to...

Claims

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Application Information

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IPC IPC(8): A61K31/445C12Q1/34A61P3/00
CPCC12Q1/34G01N2800/52G01N2800/04G01N2333/94A61P3/00
Inventor BENJAMIN, ELFRIDADO, HUNG V.WU, XIAOYANGFLANAGAN, JOHNWUSTMAN, BRANDON
Owner AMICUS THERAPEUTICS INC
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