TY - JOUR
T1 - Evaluation of non-reducing end pathologic glycosaminoglycan detection method for monitoring therapeutic response to enzyme replacement therapy in human mucopolysaccharidosis I
AU - Vera, Moin U.
AU - Le, Steven Q.
AU - Victoroff, Alla
AU - Passage, Merry B.
AU - Brown, Jillian R.
AU - Crawford, Brett E.
AU - Polgreen, Lynda E.
AU - Chen, Agnes H.
AU - Dickson, Patricia I.
N1 - Funding Information:
This work was supported by Zacharon Pharmaceuticals , the National Institute of Neurological Disorders and Stroke ( SBIR R43 NS077513 ), and the Lysosomal Disease Network . The Lysosomal Disease Network (LDN) U54-NS065768 is a part of the National Institute of Health (NIH) Rare Diseases Clinical Research Network , supported through collaboration between the NIH Office of Rare Diseases Research at the National Center for Advancing Translational Science , the National Institute of Neurological Disorders and Stroke (NINDS), and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2020/2
Y1 - 2020/2
N2 - Therapeutic development and monitoring require demonstration of effects on disease phenotype. However, due to the complexity of measuring clinically-relevant effects in rare multisystem diseases, robust biomarkers are essential. For the mucopolysaccharidoses (MPS), the measurement of glycosaminoglycan levels is relevant as glycosaminoglycan accumulation is the primary event that occurs due to reduced lysosomal enzyme activity. Traditional dye-based assays that measure total glycosaminoglycan levels have a high background, due to a normal, baseline glycosaminoglycan content in unaffected individuals. An assay that selectively detects the disease-specific non-reducing ends of heparan sulfate glycosaminoglycans that remain undegraded due to deficiency of a specific enzyme in the catabolic pathway avoids the normal background, increasing sensitivity and specificity. We evaluated glycosaminoglycan content by dye-based and non-reducing end methods using urine, serum, and cerebrospinal fluid from MPS I human samples before and after treatment with intravenous recombinant human alpha-L-iduronidase. We found that both urine total glycosaminoglycans and serum heparan sulfate derived non-reducing end levels were markedly decreased compared to baseline after 26 weeks and 52 weeks of therapy, with a significantly greater percentage reduction in serum non-reducing end (89.8% at 26 weeks and 81.3% at 52 weeks) compared to urine total glycosaminoglycans (68.3% at 26 weeks and 62.4% at 52 weeks, p < 0.001). Unexpectedly, we also observed a decrease in non-reducing end levels in cerebrospinal fluid in all five subjects for whom samples were collected (mean 41.8% reduction, p = 0.01). The non-reducing ends in cerebrospinal fluid showed a positive correlation with serum non-reducing end levels in the subjects (r2 = 0.65, p = 0.005). Results suggest utility of the non-reducing end assay in evaluating a therapeutic response in MPS I.
AB - Therapeutic development and monitoring require demonstration of effects on disease phenotype. However, due to the complexity of measuring clinically-relevant effects in rare multisystem diseases, robust biomarkers are essential. For the mucopolysaccharidoses (MPS), the measurement of glycosaminoglycan levels is relevant as glycosaminoglycan accumulation is the primary event that occurs due to reduced lysosomal enzyme activity. Traditional dye-based assays that measure total glycosaminoglycan levels have a high background, due to a normal, baseline glycosaminoglycan content in unaffected individuals. An assay that selectively detects the disease-specific non-reducing ends of heparan sulfate glycosaminoglycans that remain undegraded due to deficiency of a specific enzyme in the catabolic pathway avoids the normal background, increasing sensitivity and specificity. We evaluated glycosaminoglycan content by dye-based and non-reducing end methods using urine, serum, and cerebrospinal fluid from MPS I human samples before and after treatment with intravenous recombinant human alpha-L-iduronidase. We found that both urine total glycosaminoglycans and serum heparan sulfate derived non-reducing end levels were markedly decreased compared to baseline after 26 weeks and 52 weeks of therapy, with a significantly greater percentage reduction in serum non-reducing end (89.8% at 26 weeks and 81.3% at 52 weeks) compared to urine total glycosaminoglycans (68.3% at 26 weeks and 62.4% at 52 weeks, p < 0.001). Unexpectedly, we also observed a decrease in non-reducing end levels in cerebrospinal fluid in all five subjects for whom samples were collected (mean 41.8% reduction, p = 0.01). The non-reducing ends in cerebrospinal fluid showed a positive correlation with serum non-reducing end levels in the subjects (r2 = 0.65, p = 0.005). Results suggest utility of the non-reducing end assay in evaluating a therapeutic response in MPS I.
KW - Enzyme replacement therapy
KW - Glycosaminoglycan
KW - Hurler
KW - Lysosomal storage disorder
KW - Mucopolysaccharidosis
UR - http://www.scopus.com/inward/record.url?scp=85073755307&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2019.09.001
DO - 10.1016/j.ymgme.2019.09.001
M3 - Article
C2 - 31630958
AN - SCOPUS:85073755307
VL - 129
SP - 91
EP - 97
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
SN - 1096-7192
IS - 2
ER -