Heparin cofactor II–thrombin complex: A biomarker of MPS disease

Randall, Derrick R.; Colobong, Karen E.; Hemmelgarn, Harmony; Sinclair, Graham; Hetty, Elly; Thomas, Anita C; Bodamer, Olaf A.; Volkmar, Barbara; Fernhoff, Paul M.; Casey, Robin; Chan, Alicia; Mitchell, Grant A.; Stockler, Silvia; Mélancon, Serge B.; Rupar, Tony; Clarke, Lorne A.

doi:10.1016/j.ymgme.2008.05.001

Cited by 57 publications

(47 citation statements)

References 25 publications

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“…Thus, one explanation for the severe neuropathology in some MPS disorders may be that overall lysosomal storage breaches a critical threshold where cellular processes such as autophagy are more dramatically affected. It is also important to note that, like heparan sulfate, dermatan sulfate is a bioactive polymer that can inhibit lysosomal enzyme activities (40), modulate enzyme activities in the serum such as serpin-protease complex formation (41,42), and regulate growth factor signaling and inflammatory response (43). Thus, in addition to contributing to the overall lysosomal load, storage of dermatan sulfate in Sanfilippo could affect biological processes that influence pathology.…”

Section: Discussionmentioning

confidence: 99%

“…For example, the dermatan sulfate sensitivity of the heparin cofactor II-thrombin complex formation has been used to detect MPS disorders where this glycosaminoglycan is stored (41,42,44). Initial testing of this diagnostic in MPS patients demonstrated the robustness of the assay for detecting MPS disorders where dermatan sulfate catabolism is known to be deficient.…”

Section: Discussionmentioning

confidence: 99%

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Secondary Storage of Dermatan Sulfate in Sanfilippo Disease

Lamanna

Lawrence

Sarrazin

et al. 2011

Journal of Biological Chemistry

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Mucopolysaccharidoses are a group of genetically inherited disorders that result from the defective activity of lysosomal enzymes involved in glycosaminoglycan catabolism, causing their intralysosomal accumulation. Sanfilippo disease describes a subset of mucopolysaccharidoses resulting from defects in heparan sulfate catabolism. Sanfilippo disorders cause severe neuropathology in affected children. The reason for such extensive central nervous system dysfunction is unresolved, but it may be associated with the secondary accumulation of metabolites such as gangliosides. In this article, we describe the accumulation of dermatan sulfate as a novel secondary metabolite in Sanfilippo. Based on chondroitinase ABC digestion, chondroitin/dermatan sulfate levels in fibroblasts from Sanfilippo patients were elevated 2-5-fold above wild-type dermal fibroblasts. Lysosomal turnover of chondroitin/dermatan sulfate in these cell lines was significantly impaired but could be normalized by reducing heparan sulfate storage using enzyme replacement therapy. Examination of chondroitin/dermatan sulfate catabolic enzymes showed that heparan sulfate and heparin can inhibit iduronate 2-sulfatase. Analysis of the chondroitin/dermatan sulfate fraction by chondroitinase ACII digestion showed dermatan sulfate storage, consistent with inhibition of iduronate 2-sulfatase. The discovery of a novel storage metabolite in Sanfilippo patients may have important implications for diagnosis and understanding disease pathology.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Secondary Storage of Dermatan Sulfate in Sanfilippo Disease

Lamanna

Lawrence

Sarrazin

et al. 2011

Journal of Biological Chemistry

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“…28,29 HCII-T presence was tested on the serum of treated and control animals by Western blot analysis. Reduction of HCII-T complex down to WT levels was observed in the serum of GT mice ( Figure 2E), further confirming that metabolic correction was attained.…”

Section: Supranormal Enzymatic Activity Allows Metabolic Correction Imentioning

confidence: 99%

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model

Visigalli

Delai

Politi

et al. 2010

Blood

160

157

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Type I mucopolysaccharidosis (MPS I) IntroductionType I mucopolysaccharidosis (MPS I) is one of the most frequent lysosomal storage disorders (LSDs) and is due to the inherited deficiency of ␣-L-iduronidase (IDUA) activity, which results in the accumulation of its unprocessed substrates (glycosaminoglycans; GAGs) in many organs. 1 The disorder is systemic and clinically heterogeneous. Clinical manifestations include skeletal dysplasia, joint stiffness, visual and auditory defects, cardiac insufficiency, hepatosplenomegaly, and mental retardation. The clinical spectrum ranges from the severe Hurler syndrome (MPS I-H) to the attenuated Scheie syndrome. Mental retardation is distinctive only of MPS I-H, which is fatal in childhood if untreated, thus representing the variant with the most urgent need for new therapies. Enzyme replacement therapy (ie, parenteral administration of exogenous enzyme that can be internalized by tissue cells via the mannosium-6-phosphate receptor) is recommended only for MPS I patients without primary neurologic disease, due to the inability of the enzyme to efficiently cross the blood-brain barrier; moreover, neutralizing antibodies can attenuate its efficacy. 2 When performed at early ages, hematopoietic stem cell (HSC) transplantation (HCT) from healthy donors alleviates most disease manifestations in MPS I-H patients, likely by migration of the transplant-derived leukocytes into organs, where they can clear the storage and secrete the functional enzyme for correction of the metabolic defect in resident cells. 3 However, despite recent improvements in the outcome of HCT, the morbidity and mortality associated with the procedure are still not negligible, mostly due to rejection and graft-versus-host disease. Moreover, the amount of enzyme that transplantation can provide to the organism can be limiting, especially since donors are often heterozygous siblings. Indeed, a relationship between circulating enzyme levels after transplant and urinary GAGs has been shown 4 : the low enzyme levels achieved with heterozygote donor transplant lead to less adequate reduction in GAG levels. Likely due to partial metabolic correction at disease sites, the impact of HCT on central nervous system (CNS) and skeletal disease, despite being substantial in ameliorating patients' phenotype, could still benefit from further improvement. 5 The benefits of different gene therapy approaches were established in MPS I animal models. Intravenous delivery of viral vectors, which can establish a tissue source for systemic enzyme distribution, was effective in controlling disease manifestations in The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org From MPS I animal models upon neonatal treatment. [6][7][8][9] However, residu...

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“…Formation of the covalent complex between heparin cofactor II and thrombin is catalyzed by GAGs such as dermatan sulfate, and serum concentrations of this complex have been suggested as a biomarker for MPS I (25,26). Serum concentrations of the heparin cofactor II-thrombin complex (HCII-T) were measured by ELISA (Fig.…”

Section: Resultsmentioning

confidence: 99%

Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I

Hinderer

Bell

Gurda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Patients with mucopolysaccharidosis type I (MPS I), a genetic deficiency of the lysosomal enzyme α-l-iduronidase (IDUA), exhibit accumulation of glycosaminoglycans in tissues, with resulting diverse clinical manifestations including neurological, ocular, skeletal, and cardiac disease. MPS I is currently treated with hematopoietic stem cell transplantation or weekly enzyme infusions, but these therapies have significant drawbacks for patient safety and quality of life and do not effectively address some of the most critical clinical sequelae, such as life-threatening cardiac valve involvement. Using the naturally occurring feline model of MPS I, we tested liver-directed gene therapy as a means of achieving longterm systemic IDUA reconstitution. We treated four MPS I cats at 3-5 mo of age with an adeno-associated virus serotype 8 vector expressing feline IDUA from a liver-specific promoter. We observed sustained serum enzyme activity for 6 mo at ∼30% of normal levels in one animal, and in excess of normal levels in three animals. Remarkably, treated animals not only demonstrated reductions in glycosaminoglycan storage in most tissues, but most also exhibited complete resolution of aortic valve lesions, an effect that has not been previously observed in this animal model or in MPS I patients treated with current therapies. These data point to clinically meaningful benefits of the robust enzyme expression achieved with hepatic gene transfer that extend beyond the economic and quality of life advantages over lifelong enzyme infusions.

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Heparin cofactor II–thrombin complex: A biomarker of MPS disease

Cited by 57 publications

References 25 publications

Secondary Storage of Dermatan Sulfate in Sanfilippo Disease

Secondary Storage of Dermatan Sulfate in Sanfilippo Disease

Gene therapy augments the efficacy of hematopoietic cell transplantation and fully corrects mucopolysaccharidosis type I phenotype in the mouse model

Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I

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