Evaluation of non-reducing end pathologic glycosaminoglycan detection method for monitoring therapeutic response to enzyme replacement therapy in human mucopolysaccharidosis I.
Mol Genet Metab
; 129(2): 91-97, 2020 02.
Article
in En
| MEDLINE
| ID: mdl-31630958
ABSTRACT
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 26â¯weeks and 52â¯weeks of therapy, with a significantly greater percentage reduction in serum non-reducing end (89.8% at 26â¯weeks and 81.3% at 52â¯weeks) compared to urine total glycosaminoglycans (68.3% at 26â¯weeks and 62.4% at 52â¯weeks, pâ¯<â¯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, pâ¯=â¯0.01). The non-reducing ends in cerebrospinal fluid showed a positive correlation with serum non-reducing end levels in the subjects (r2â¯=â¯0.65, pâ¯=â¯0.005). Results suggest utility of the non-reducing end assay in evaluating a therapeutic response in MPS I.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Mucopolysaccharidosis I
/
Enzyme Replacement Therapy
/
Glycosaminoglycans
Type of study:
Diagnostic_studies
/
Evaluation_studies
Limits:
Humans
Language:
En
Journal:
Mol Genet Metab
Journal subject:
BIOLOGIA MOLECULAR
/
BIOQUIMICA
/
METABOLISMO
Year:
2020
Document type:
Article
Affiliation country:
United States