Methods of diagnosing a disease and methods of monitoring treatment of a disease by quantifying a non-reducing end glycan residual compound and comparing to a second biomarker

Abstract

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

1 .- 26 . (canceled) 
     
     
         27 . A method of determining in an individual the presence, identity, and/or severity of mucopolysaccharidosis (MPS) III, 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 III relative to individuals without MPS III, 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 III relative to individuals without the MPS III, and wherein: 
 1) the second biomarker is a reducing end biomarker, 
 2) the second biomarker is an internal glycan biomarker, or 
 3) when the MPS III 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 III.   
     
     
         28 . The method of  claim 27 , wherein the population of glycans comprises a glycan selected from the group consisting of chondroitin sulfate, dermatan sulfate, and heparan sulfate. 
     
     
         29 . The method of  claim 27 , wherein the MPS is MPS IIIA, MPS IIIB, MPS IIIC, or MPS IIID, and wherein:
 a. when the MPS is MPS IIIA, first biomarker is selected from the group consisting of GlcNS, GlcNS6S-UA2S-GlcNAc6S, GlcNS-UA-GlcNAc, GlcNS-UA2S-GlcNAc6S, GlcNS6S-UA-GlcNAc6S, GlcNS6S-UA2S-GlcNAc, GlcNS6S-UA-GlcNAc, GlcNS-UA2S-GlcNAc, GlcNS, GlcNS-UA-GlcNAc6S, GlcNS6S-UA2S-GlcNS6S, GlcNS-UA-GlcNS, GlcNS-UA2S-GlcNS6S, GlcNS6S-UA-GlcNS6S, GlcNS6S-UA2S-GlcNS, GlcNS6S-UA-GlcNS, GlcNS-UA2S-GlcNS, GlcNS, GlcNS-UA-GlcNS6S;   b. when the MPS is MPS IIIB, first biomarker is selected from the group consisting of GlcNAc, GlcNAc-UA2S-GlcNAc6S, GlcNAc-UA-GlcNAc, GlcNAc-UA2S-GlcNAc, GlcNAc-UA-GlcNAc6S, GlcNAc-UA2S-GlcNS6S, GlcNAc-UA-GlcNS, GlcNAc-UA2S-GlcNS, GlcNAc-UA-GlcNS6S;   c. when the MPS is MPS IIIC, first biomarker is selected from the group consisting of GlcN, GlcN6S-UA2S-GlcNAc6S, GlcN-UA-GlcNAc, GlcN-UA2S-GlcNAc6S, GlcN6S-UA-GlcNAc, GlcN6S-UA2S-GlcNAc, GlcN6S-UA-GlcNAc, GlcN-UA2S-GlcNAc, GlcN-UA-GlcNAc6S, GlcN6S-UA2S-GlcNS6S, GlcN-UA-GlcNS, GlcN-UA2S-GlcNS6S, GlcN6S-UA-GlcNS6S, GlcN6S-UA2S-GlcNS, GlcN6S-UA-GlcNS, GlcN-UA2S-GlcNS, GlcN-UA-GlcNS6S; and   d. when the MPS is MPS IIID, first biomarker is selected from the group consisting of GlcN6S, GlcNAc6S, GlcN6S-UA2S-GlcNAc6S, GlcN6S-UA-GlcNAc, GlcN6S-UA2S-GlcNAc, GlcN6S-UA-GlcNAc6S. GlcNAc6S-UA2S-GlcNAc6S, GlcNAc6S-UA-GlcNAc, GlcNAc6S-UA2S-GlcNAc, GlcNAc6S-UA-GlcNAc6S, GlcN6S-UA2S-GlcNS6S, GlcN6S-UA-GlcNS, GlcN6S-UA2S-GlcNS, GlcN6S-UA-GlcNS6S, GlcNAc6S-UA2S-GlcNS6S, GlcNAc6S-UA-GlcNS, GlcNAc6S-UA2S-GlcNS, GlcNAc6S-UA-GlcNS6S.   
     
     
         30 . The method of  claim 29 , wherein the MPS is MPS IIIA, and wherein the first biomarker is selected from the group consisting of GlcNS and GlcNS-UA2S, -GlcNS. 
     
     
         31 . The method of  claim 29 , wherein the MPS is MPS IIIB, and wherein the first biomarker is GlcNAc-UA2S-GlcNS. 
     
     
         32 . The method of  claim 29 , wherein the MPS is MPS IIIC, and wherein the first biomarker is selected from the group consisting of GlcN-UA2S-GlcNS6S and GlcN6S-UA-GlcNS6S. 
     
     
         33 . The method of  claim 29 , wherein the MPS is MPS IIID, and wherein the first biomarker is GlcN6S. 
     
     
         34 . The method of  claim 27 , wherein the MPS is MPS IIIA, MPS IIIB, MPS IIIC, or MPS IIID, and wherein:
 a. when the MPS is MPS IIIA, the second biomarker is selected from the group consisting of GlcNS, GlcNS6S-UA2S-GlcNAc6S, GlcNS-UA-GlcNAc, GlcNS-UA2S-GlcNAc6S, GlcNS6S-UA-GlcNAc6S, GlcNS6S-UA2S-GlcNAc, GlcNS6S-UA-GlcNAc, GlcNS-UA2S-GlcNAc, GlcNS, GlcNS-UA-GlcNAc6S, GlcNS6S-UA2S-GlcNS6S, GlcNS-UA-GlcNS, GlcNS-UA2S-GlcNS6S, GlcNS6S-UA-GlcNS6S, GlcNS6S-UA2S-GlcNS, GlcNS6S-UA-GlcNS, GlcNS-UA2S-GlcNS, GlcNS, GlcNS-UA-GlcNS6S, GlcN, GlcN6S-UA2S-GlcNAc6S, GlcN-UA-GlcNAc, GlcN-UA2S-GlcNAc6S, GlcN6S-UA-GlcNAc, GlcN6S-UA2S-GlcNAc, GlcN6S-UA-GlcNAc, GlcN-UA2S-GlcNAc, GlcN-UA-GlcNAc6S, GlcN6S-UA2S-GlcNS6S, GlcN-UA-GlcNS, GlcN-UA2S-GlcNS6S, GlcN6S-UA-GlcNS6S, GlcN6S-UA2S-GlcNS, GlcN6S-UA-GlcNS, GlcN-UA2S-GlcNS, GlcN-UA-GlcNS6S, 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, ΔUA2S-GlcNS6S3S, ΔUA-GalNAc, ΔUA-GalNAc4S, ΔUA-GalNAc6S, ΔUA2S-GalNAc, ΔUA2S-GalNAc4S, ΔUA2S-GalNAc6S, ΔUA-GalNAc4S6S, ΔUA2S-GalNAc4S6S;   b. when the MPS is MPS IIIB, the second biomarker is selected from the group consisting of IdoA-GlcNS, IdoA-GlcNS6S, IdoA-GlcNAc, IdoA-GlcNAc6S, IdoA-GalNAc4S, IdoA-GalNAc6S, IdoA-GalNAc, IdoA-GalNAc4S6S, IdoA2S-GlcNS, IdoA2S-GlcNS6S, IdoA2S-GlcNAc, IdoA2S-GlcNAc6S, IdoA2S-GalNAc4S, IdoA2S-GalNAc6S, IdoA2S-GalNAc, IdoA2S-GalNAc4S6S GlcNAc, GlcNAc-UA2S-GlcNAc6S, GlcNAc-UA-GlcNAc, GlcNAc-UA2S-GlcNAc, GlcNAc-UA-GlcNAc6S, GlcNAc-UA2S-GlcNS6S, GlcNAc-UA-GlcNS, GlcNAc-UA2S-GlcNS, GlcNAc-UA-GlcNS6S, GlcA-GlcNAc, GlcA-GlcNS, GlcA-GlcNAc6S, GlcA-GlcNS6S, GlcA-GalNAc, GlcA-GalNAc4S, GlcA-GalNAc6S, GlcA-GalNAc4S6S, Gal-GlcNAc, Gal-GlcNAc6S, Gal6S-GlcNAc, Gal6S-GlcNAc6S, GlcNAc-Gal, GlcNAc-Gal6S, GlcNAc6S-Gal, GlcNAc6S-Gal6S, 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, ΔUA2S-GlcNS6S3S, ΔUA-GalNAc, ΔUA-GalNAc4S, ΔUA-GalNAc6S, ΔUA2S-GalNAc, ΔUA2S-GalNAc4S, ΔUA2S-GalNAc6S, ΔUA-GalNAc4S6S, ΔUA2S-GalNAc4S6S;   c. when the MPS is MPS IIIC, the second biomarker is selected from the group consisting of GlcNAc, GlcNAc-UA2S-GlcNAc6S, GlcNAc-UA-GlcNAc, GlcNAc-UA2S-GlcNAc, GlcNAc-UA-GlcNAc6S, GlcNAc-UA2S-GlcNS6S, GlcNAc-UA-GlcNS, GlcNAc-UA2S-GlcNS, GlcNAc-UA-GlcNS6S, GlcN, GlcN6S-UA2S-GlcNAc6S, GlcN-UA-GlcNAc, GlcN-UA2S-GlcNAc6S, GlcN6S-UA-GlcNAc, GlcN6S-UA2S-GlcNAc, GlcN6S-UA-GlcNAc, GlcN-UA2S-GlcNAc, GlcN-UA-GlcNAc6S, GlcN6S-UA2S-GlcNS6S, GlcN-UA-GlcNS, GlcN-UA2S-GlcNS6S, GlcN6S-UA-GlcNS6S, GlcN6S-UA2S-GlcNS, GlcN6S-UA-GlcNS, GlcN-UA2S-GlcNS, GlcN-UA-GlcNS6S, 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, ΔUA2S-GlcNS6S3S, ΔUA-GalNAc, ΔUA-GalNAc4S, ΔUA-GalNAc6S, ΔUA2S-GalNAc, ΔUA2S-GalNAc4S, ΔUA2S-GalNAc6S, ΔUA-GalNAc4S6S, ΔUA2S-GalNAc4S6S; and   d. when the MPS is MPS IIID, the second biomarker is selected from the group consisting of GlcNAc, GlcNAc-UA2S-GlcNAc6S, GlcNAc-UA-GlcNAc, GlcNAc-UA2S-GlcNAc, GlcNAc-UA-GlcNAc6S, GlcNAc-UA2S-GlcNS6S, GlcNAc-UA-GlcNS, GlcNAc-UA2S-GlcNS, GlcNAc-UA-GlcNS6S, GlcN, GlcN6S-UA2S-GlcNAc6S, GlcN-UA-GlcNAc, GlcN-UA2S-GlcNAc6S, GlcN6S-UA-GlcNAc6S, GlcN6S-UA2S-GlcNAc, GlcN6S-UA-GlcNAc, GlcN-UA2S-GlcNAc, GlcN-UA-GlcNAc6S, GlcN6S-UA2S-GlcNS6S, GlcN-UA-GlcNS, GlcN-UA2S-GlcNS6S, GlcN6S-UA-GlcNS6S, GlcN6S-UA2S-GlcNS, GlcN6S-UA-GlcNS, GlcN-UA2S-GlcNS, GlcN-UA-GlcNS6S, GlcN6S, GlcNAc6S, GlcN6S-UA2S-GlcNAc6S, GlcN6S-UA-GlcNAc, GlcN6S-UA2S-GlcNAc, GlcN6S-UA-GlcNAc6S, GlcNAc6S-UA2S-GlcNAc6S, GlcNAc6S-UA-GlcNAc, GlcNAc6S-UA2S-GlcNAc, GlcNAc6S-UA-GlcNAc6S, GlcN6S-UA2S-GlcNS6S, GlcN6S-UA-GlcNS, GlcN6S-UA2S-GlcNS, GlcN6S-UA-GlcNS6S, GlcNAc6S-UA2S-GlcNS6S, GlcNAc6S-UA-GlcNS, GlcNAc6S-UA2S-GlcNS, GlcNAc6S-UA-GlcNS, 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, ΔUA2S-GlcNS6S3S, ΔUA-GalNAc, ΔUA-GalNAc4S, ΔUA-GalNAc6S, ΔUA2S-GalNAc, ΔUA2S-GalNAc4S, ΔUA2S-GalNAc6S, ΔUA-GalNAc4S6S, ΔUA2S-GalNAc4S6S.   
     
     
         35 . The method of  claim 34 , wherein the MPS is MPS IIIA, the first biomarker is GlcNS, and the second biomarker is GlcNS-UA2S-GlcNS. 
     
     
         36 . The method of  claim 34 , wherein the MPS is MPS IIIC, and wherein the first biomarker is GlcN-UA2S-GlcNS6S and the second biomarker is GlcN6S-UA-GlcNS6S. 
     
     
         37 . The method of  claim 27 , wherein the at least one digesting glycan enzyme is selected from the group consisting of N-sulfatase, heparin lyase, hexosaminidase, deacetylase, 6-O sulfatase, N-acetyl glucosaminidase, glucosamine N-acetyltransferase and N-acetyl transferase. 
     
     
         38 . A method of determining in an individual the presence, identity, and/or severity of mucopolysaccharidosis (MPS) III, 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 III relative to individuals without MPS III, 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 III relative to individuals without the MPS III, 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 III 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 III.