IP Library › Granted Patent US 9,915,649
Granted Patent B2
US 9,915,649 · App. 15/097,218 · Granted Mar 13, 2018

Methods of determining the presence, identity, and/or severity of mucopolysaccharidosis (MPS) VI and IVA

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Quick Facts
Patent No.
US 9,915,649
App. No.
15/097,218
Granted
Mar 13, 2018
Kind
B2
Abstract

Provided herein are methods of diagnosing or monitoring the treatment of abnormal glycan accumulation or a disorder associated with abnormal glycan accumulation.

Claims (58)

1. A method of determining in an individual the presence, identity, and/or severity of mucopolysaccharidosis (MPS) VI, the method comprising:

(a) generating a first biomarker comprising a glycan residual compound, wherein the first biomarker is generated by treating a population of glycans, in or isolated from a biological sample from the individual, with at least one digesting glycan enzyme,

wherein prior to enzyme treatment, the first biomarker is not present in abundance in samples from individuals with MPS VI relative to individuals without MPS VI, and wherein the first biomarker is a non-reducing end (NRE) biomarker;

(b) generating a second biomarker comprising a glycan residual compound, wherein the second biomarker is generated by treating a population of glycans, in or isolated from a biological sample from the individual, with at least one digesting glycan enzyme,

wherein prior to enzyme treatment, the second biomarker is not present in abundance in samples from individuals with the MPS VI relative to individuals without the MPS VI, and wherein:

1) the second biomarker is an NRE biomarker different from the first biomarker,

2) the second biomarker is a reducing end biomarker,

3) the second biomarker is an internal glycan biomarker, or

4) when the MPS VI is caused by an abnormal function of a glycan degradation enzyme in the individual, the second biomarker is generated by treating the first biomarker with the glycan degradation enzyme that is functioning abnormally in the individual;

(c) detecting the presence of and/or measuring the amount of the first and second biomarker produced and displaying or recording the presence of or a measure of a population of the first and second biomarkers by using an analytical instrument; and

(d) monitoring and/or comparing the amounts of the first and second biomarkers in a biological sample;

wherein the presence of and/or measure of the amounts of the first and second biomarkers are utilized to determine the presence, identity, and/or severity of MPS VI; and

wherein the population of glycans comprises a glycan selected from the group consisting of keratan sulfate, chondroitin sulfate, dermatan sulfate, and heparan sulfate.

2. The method of claim 1 , wherein the first biomarker is selected from the group consisting of GalNAc4S, GalNAc4S-UA-GalNAc, GalNAc4S-UA-GalNAc4S, GalNAc4S-UA-GalNAc6S, GalNAc4S-UA-GalNAc4S6S, GalNAc4S-UA2S-GalNAc, GalNAc4S-UA2S-GalNAc4S, GalNAc4S-UA2S-GalNAc6S, and GalNAc4S-UA2S-GalNAc4S6S.

3. The method of claim 2 , wherein the first biomarker is GalNAc4S.

4. The method of claim 2 , wherein the second biomarker is selected from the group consisting of a sulfated NRE biomarker, an internal glycan biomarker, and a non-sulfated NRE biomarker.

5. The method of claim 2 , wherein the second biomarker is selected from the group consisting of GalNAc6S, GalNAc6S4S, GalNAc6S-UA-GalNAc, GalNAc6S-UA-GalNAc4S, GalNAc6S-UA-GalNAc6S, GalNAc6S-UA-GalNAc4S6S, GalNAc6S-UA2S-GalNAc, GalNAc6S-UA2S-GalNAc4S, GalNAc6S-UA2S-GalNAc6S, GalNAc6S-UA2S-GalNAc4S6S, GalNAc6S4S-UA-GalNAc, GalNAc6S4S-UA-GalNAc4S, GalNAc6S4S-UA-GalNAc6S, GalNAc6S4S-UA-GalNAc4S6S, GalNAc6S4S-UA2S-GalNAc, GalNAc6S4S-UA2S-GalNAc4S, GalNAc6S4S-UA2S-GalNAc6S, GalNAc6S4S-UA2S-GalNAc4S6S, Gal6S, Gal6S-GlcNAc, Gal6S-GlcNAc6S, Gal6S-GlcNAc-Gal, Gal6S-GlcNAc-Gal6S, Gal6S-GlcNAc6S-Gal, and Gal6S-GlcNAc6S-Gal6S.

6. The method of claim 5 , wherein the first biomarker is GalNAc 4 S.

7. The method of claim 2 , wherein the second biomarker is selected from the group consisting of ΔUA-GalNAc, ΔUA-GalNAc4S, ΔUA-GalNAc6S, ΔUA2S-GalNAc, ΔUA2S-GalNAc4S, ΔUA2S-GalNAc6S, ΔUA-GalNAc4S6S, ΔUA2S-GalNAc4S6S, ΔUA-GlcN, ΔUA-GlcN6S, ΔUA2S-GlcN, ΔUAS-GlcN6S, ΔUA-GlcNAc, ΔUA-GlcNAc6S, ΔUA2S-GlcNAc, ΔUA2S-GlcNAc6S, ΔUA-GlcNS, ΔUA-GlcNS6S, ΔUA-GlcNS3S, ΔUA2S-GlcNS, ΔUA2S-GlcNS6S, ΔUA2S-GlcNS3S, ΔUA-GlcNS6S3S, and ΔUA2S-GlcNS6S3S.

8. The method of claim 7 , wherein the first biomarker is GalNAc4S.

9. The method of claim 2 , wherein the second biomarker is selected from the group consisting of GalNAc, GalNAc-UA-GalNAc, GalNAc-UA-GalNAc4S, GalNAc-UA-GalNAc6S, GalNAc-UA-GalNAc4S6S, GalNAc-UA2S-GalNAc, GalNAc-UA2S-GalNAc4S, GalNAc-UA2S-GalNAc6S, GalNAc-UA2S-GalNAc4S6S, Gal, Gal-GlcNAc, Gal-GlcNAc6S, Gal-GlcNAc-Gal, Gal-GlcNAc-Gal6S, Gal-GlcNAc6S-Gal, and Gal-GlcNAc6S-Gal6S.

10. The method of claim 9 , wherein the first biomarker is GalNAc4S.

11. The method of claim 2 , wherein the first biomarker is GalNAc4S and the second biomarker is GalNAc6S.

12. A method of determining in an individual the presence, identity, and/or severity of MPS IVA, the method comprising:

(a) generating a first biomarker comprising a glycan residual compound, wherein the first biomarker is generated by treating a population of glycans, in or isolated from a biological sample from the individual, with at least one digesting glycan enzyme,

wherein prior to enzyme treatment, the first biomarker is not present in abundance in samples from individuals with MPS IVA relative to individuals without MPS IVA, and wherein the first biomarker is an NRE biomarker;

(b) generating a second biomarker comprising a glycan residual compound, wherein the second biomarker is generated by treating a population of glycans, in or isolated from a biological sample from the individual, with at least one digesting glycan enzyme,

wherein prior to enzyme treatment, the second biomarker is not present in abundance in samples from individuals with the MPS IVA relative to individuals without the MPS IVA, and wherein:

1) the second biomarker is an NRE biomarker different from the first biomarker,

2) the second biomarker is a reducing end biomarker,

3) the second biomarker is an internal glycan biomarker, or

4) when the MPS IVA is caused by an abnormal function of a glycan degradation enzyme in the individual, the second biomarker is generated by treating the first biomarker with the glycan degradation enzyme that is functioning abnormally in the individual;

(c) detecting the presence of and/or measuring the amount of the first and second biomarker produced and displaying or recording the presence of or a measure of a population of the first and second biomarkers by using an analytical instrument; and

(d) monitoring and/or comparing the amounts of the first and second biomarkers in a biological sample;

wherein the presence of and/or measure of the amounts of the first and second biomarkers are utilized to determine the presence, identity, and/or severity of MPS IVA; and

wherein the population of glycans comprises a glycan selected from the group consisting of keratan sulfate, chondroitin sulfate, dermatan sulfate, and heparan sulfate.

13. The method of claim 12 , wherein the first biomarker is selected from the group consisting of GalNAc6S, GalNAc6S4S, GalNAc6S-UA-GalNAc, GalNAc6S-UA-GalNAc4S, GalNAc6S-UA-GalNAc6S, GalNAc6S-UA-GalNAc4S6S, GalNAc6S-UA2S-GalNAc, GalNAc6S-UA2S-GalNAc4S, GalNAc6S-UA2S-GalNAc6S, GalNAc6S-UA2S-GalNAc4S6S, GalNAc6S4S-UA-GalNAc, GalNAc6S4S-UA-GalNAc4S, GalNAc6S4S-UA-GalNAc6S, GalNAc6S4S-UA-GalNAc4S6S, GalNAc6S4S-UA2S-GalNAc, GalNAc6S4S-UA2S-GalNAc4S, GalNAc6S4S-UA2S-GalNAc6S, GalNAc6S4S-UA2S-GalNAc4S6S, Gal6S, Gal6S-GlcNAc, Gal6S-GlcNAc6S, Gal6S-GlcNAc-Gal, Gal6S-GlcNAc-Gal6S, Gal6S-GlcNAc6S-Gal, and Gal6S-GlcNAc6S-Gal6S.

14. The method of claim 13 , wherein the first biomarker is GalNAc6S.

15. The method of claim 13 , wherein the second biomarker is selected from the group consisting of a sulfated NRE biomarker, an internal glycan biomarker, and a non-sulfated NRE biomarker.

16. The method of claim 13 , wherein the second biomarker is selected from the group consisting of GalNAc4S, GalNAc4S-UA-GalNAc, GalNAc4S-UA-GalNAc4S, GalNAc4S-UA-GalNAc6S, GalNAc4S-UA-GalNAc4S6S, GalNAc4S-UA2S-GalNAc, GalNAc4S-UA2S-GalNAc4S, GalNAc4S-UA2S-GalNAc6S, and GalNAc4S-UA2S-GalNAc4S6S.

17. The method of claim 16 , wherein the first biomarker is GalNAc6S.

18. The method of claim 13 , wherein the second biomarker is selected from the group consisting of ΔUA-GalNAc, ΔUA-GalNAc4S, ΔUA-GalNAc6S, ΔUA2S-GalNAc, ΔUA2S-GalNAc4S, ΔUA2S-GalNAc6S, ΔUA-GalNAc4S6S, ΔUA2S-GalNAc4S6S, ΔUA-GlcN, ΔUA-GlcN6S, ΔUA2S-GlcN, ΔUAS-GlcN6S, ΔUA-GlcNAc, ΔUA-GlcNAc6S, ΔUA2S-GlcNAc, ΔUA2S-GlcNAc6S, ΔUA-GlcNS, ΔUA-GlcNS6S, ΔUA-GlcNS3S, ΔUA2S-GlcNS, ΔUA2S-GlcNS6S, ΔUA2S-GlcNS3S, ΔUA-GlcNS6S3S, and ΔUA2S-GlcNS6S3S.

19. The method of claim 18 , wherein the first biomarker is GalNAc6S.

20. The method of claim 13 , wherein the second biomarker is selected from the group consisting of GalNAc, GalNAc-UA-GalNAc, GalNAc-UA-GalNAc4S, GalNAc-UA-GalNAc6S, GalNAc-UA-GalNAc4S6S, GalNAc-UA2S-GalNAc, GalNAc-UA2S-GalNAc4S, GalNAc-UA2S-GalNAc6S, GalNAc-UA2S-GalNAc4S6S, Gal, Gal-GlcNAc, Gal-GlcNAc6S, Gal-GlcNAc-Gal, Gal-GlcNAc-Gal6S, Gal-GlcNAc6S-Gal, and Gal-GlcNAc6S-Gal6S.

21. The method of claim 20 , wherein the first biomarker is GalNAc6S.

22. The method of claim 13 , wherein the first biomarker is GalNAc6S and the second biomarker is GalNAc4S.

23. The method of claim 1 , wherein the at least one digesting glycan enzyme is a glycosaminoglycan lyase.

24. The method of claim 1 , wherein the at least one digesting glycan enzyme is a glycosidase.

25. The method of claim 24 , wherein the glycosidase is a hexosaminidase.

26. The method of claim 25 , wherein the hexosaminidase is an N-acetyl-galactosidase.

27. The method of claim 26 , wherein the N-acetyl-galactosidase is chondroitinase ABC.

28. The method of claim 12 , wherein the at least one digesting glycan enzyme is a glycosaminoglycan lyase.

29. The method of claim 12 , wherein the at least one digesting glycan enzyme is a glycosidase.

30. The method of claim 29 , wherein the glycosidase is a hexosaminidase.

31. The method of claim 30 , wherein the hexosaminidase is an N-acetyl-galactosidase.

32. The method of claim 31 , wherein the N-acetyl-galactosidase is chondroitinase ABC.

33. The method of claim 1 , wherein the population of glycans comprises a glycan selected from the group consisting of keratan sulfate and chondroitin sulfate.

34. The method of claim 12 , wherein the population of glycans comprises a glycan selected from the group consisting of keratan sulfate and chondroitin sulfate.

Assignments (1)
SECURITY INTEREST Recorded Apr 27, 2026
From: BIOMARIN PHARMACEUTICAL INC.; AMICUS THERAPEUTICS, INC.
To: CITIBANK, N.A., AS COLLATERAL AGENT
Reel/Frame 075493/0968 →