Method to predict response to pharmacological chaperone treatment of diseases
View Patent ↗The present invention provides methods to determine whether a patient with a lysosomal storage disorder win 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.
1. A method for identifying candidate patients having Fabry Disease for drug therapy, said method comprising:
(a) identifying the mutant α-galactosidase A expressed in the patient having Fabry Disease,
(b) expressing a recombinant form of said mutant α-galactosidase A in a host cell that does not naturally express the mutant α-galactosidase A and contacting this host cell with 1-deoxygalactonojirimycin;
(c) determining the α-galactosidase A activity of the mutant α-galactosidase A in the host cell, and
(d) comparing the α-galactosidase A activity determined in (c) to the α-galactosidase A in a the host cell when it is not contacted with 1-deoxygalactonojirimycin, and
(e) determining that the patient is a candidate for treatment with 1-deoxygalactonojirimycin if:
(i) in step (d) there is a 1.3 to 40 fold increase in α-galactosidase A activity in the host cell contacted with 1-deoxygalactonojirimycin when compared to α-galactosidase A activity in the host cell not contacted with 1-deoxygalactonojirimycin, or
(ii) the α-galactosidase A activity in the host cell is at least 2% to about 100% activity of a non-mutant α-galactosidase A.
2. The method of claim 1 , wherein the host cells are human embryonic kidney (HEK) cells.
3. The method of claim 1 , wherein 1-deoxygalactonojirimycin is in a pharmaceutically acceptable salt form.
4. The method of claim 3 , wherein the pharmaceutically acceptable salt form is 1-deoxygalactonojirimycin hydrochloride.
5. The method of claim 1 , wherein the patient is female.
6. A method for treating a patient diagnosed with Fabry Disease, said method comprising administering to the patient a therapeutically effective dose of 1-deoxygalactonojirimycin, wherein the patient is identified as being a candidate for treatment with 1-deoxygalactonojirimycin by the method comprising:
(a) identifying the mutant α-galactosidase A expressed in the patient having Fabry Disease,
(b) expressing a recombinant form of said mutant α-galactosidase A in a host cell that does not naturally express the mutant α-galactosidase A and contacting this host cell with 1-deoxygalactonojirimycin;
(c) determining the α-galactosidase A activity of the mutant α-galactosidase A in the host cell,
(d) comparing the α-galactosidase A activity determined in (c) to the α-galactosidase A in a host cell when it is not contacted with 1-deoxygalactonojirimycin, and
(e) determining that the patient is a candidate for treatment with 1-deoxygalactonojirimycin if:
(i) in step (d) there is a 1.3 to 40 fold increase in α-galactosidase A activity in the host cell contacted with 1-deoxygalactonojirimycin when compared to α-galactosidase A activity in the host cell not contacted with 1-deoxygalactonojirimycin, or
(ii) the α-galactosidase A activity in the host cell is at least 2% to about 100% activity of a non-mutant α-galactosidase A.
7. The method of claim 6 , wherein the host cells are human embryonic kidney (HEK) cells.
8. The method of claim 6 , wherein 1-deoxygalactonojirimycin is in a pharmaceutically acceptable salt form.
9. The method of claim 8 , wherein the pharmaceutically acceptable salt form is 1-deoxygalactonojirimycin hydrochloride.
10. The method of claim 6 , wherein the patient is female.