METHOD FOR THE TREATMENT OF FABRY DISEASE USING PHARMACOLOGICAL CHAPERONES
The present invention provides a method treating a patient with Fabry disease by determining whether there is an improvement of a surrogate marker that is associated with Fabry disease following administration of a specific pharmacological chaperone of α-galactosidase A. The method includes administering an effective amount of 1-deoxygalactonojirimycn to the individual, wherein the 1-deoxygalactonojirimycin binds to alpha-galactosidase A in an amount effective to increase activity of the alpha-galactosidase A. The present invention also provides a method for monitoring and increasing a therapeutic response of a patient with Fabry disease following administration of a specific pharmacological chaperone of α-galactosidase A by evaluating the effect on the cytoplasmic staining pattern of a cell from the patient, wherein detection of a staining pattern in the cell that is similar to the staining pattern in a cell from a healthy individual indicates that the individual with Fabry disease is a responder.
1 - 46 . (canceled)
47 . A method for treating a patient with Fabry disease, which comprises determining whether there is an improvement of a surrogate marker that is associated with Fabry disease following administration of a specific pharmacological chaperone of α-galactosidase A.
48 . The method of claim 47 , wherein the surrogate marker is at least one selected from the group consisting of lysosomal α-galactosidase A activity in cells or tissue; GL-3 levels in kidney, heart or skin tissue; GL-3 levels urine; aberrant trafficking of α-galactosidase A in cells from Fabry patients from the ER to the lysosome; aberrant trafficking of cellular lipids though the endosomal pathway; the presence of increased amounts misfolded α-galactosidase A in the ER or cytosol; the presence of cellular stress resulting from toxic accumulation of α-galactosidase A (as determined by gene and/or protein expression of stress-related markers); aberrant endosomal pH levels; aberrant cell morphology; suppression of the ubiquitin/proteasome pathway; and an increase in the amount of ubiquitinated proteins.
49 . The method of claim 48 , wherein the surrogate marker is lysosomal α-galactosidase A activity as measured by cytoplasmic staining.
50 . The method of claim 49 , wherein lysosomal staining is detection of one or both of LAMP-1 expression and polyubiquitinated proteins.
51 . The method of claim 47 , wherein the pharmacological chaperone is 1-deoxygalactonojirimycin.
52 . A method for treating a patient with Fabry disease by adjusting the therapeutic dose of a pharmacological chaperone comprising the steps of measuring the patient's surrogate markers prior to dosing; monitoring the surrogate markers following administration of an initial dose of the pharmacological chaperone of α-galactosidase A, evaluating the effect of the dosage on the surrogate markers and adjusting the dose to obtain surrogate marker levels similar to or trend towards those found in a healthy individual.
53 . The method of claim 52 , with the further steps of measuring the patient's surrogate markers baseline levels after administering the adjusted dose of the pharmacological chaperone; evaluating the effect of the adjusted dosage on the surrogate markers and further adjusting the dose.
54 . The method of claim 52 with the further step of adjusting the dosing regimen.
55 . The method of claim 52 wherein the pharmacological chaperone is 1-deoxygalactonojirimycin.
56 . The method of claim 47 , wherein the patient is a female carrier of Fabry disease.
57 . The method of claim 52 , wherein the patient is a female carrier of Fabry disease.
58 . The method of claim 47 wherein the pharmacological chaperone binds to the alpha-galactosidase A in an amount effective to increase activity of the alpha-galactosidase A in the patient by at least about 2-fold.
59 . The method of claim 52 wherein the pharmacological chaperone binds to the alpha-galactosidase A in an amount effective to increase activity of the alpha-galactosidase A in the patient by at least about 2-fold.
60 . The method of claim 47 wherein lysosmal levels of globotriaosylceramide are reduced by at least about 2-fold.
61 . The method of claim 52 wherein lysosmal levels of globotriaosylceramide are reduced by at least about 2-fold.