Improved Metabolic Correction in Patients with Lysosomal Storage Disease Treated with Hematopoietic Stem Cell Transplant Compared with Enzyme Replacement Therapy

Wynn, Robert F.; Wraith, J. E.; Mercer, Jean; O’Meara, Anne; Tylee, Karen; Thornley, Margaret J.; Church, Heather J.; Bigger, Brian

doi:10.1016/j.jpeds.2008.11.005

Cited by 129 publications

(102 citation statements)

References 7 publications

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“…[18][19][20][21] We, therefore, studied DS/CS in our longitudinal series of patients. Total urinary GAG and DS/CS ratio were determined using two dimensional electrophoresis (originally described by Whiteman 22 ) and LabWorks software (Anachem, Luton, UK).…”

Section: Biomarkers and Chimerism Analysismentioning

confidence: 99%

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

Saif¹,

Bigger²,

Brookes³

et al. 2012

Haematologica

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BackgroundMucopolysaccharidosis type I is caused by deficiency of a-L-iduronidase. Currently available treatment options include an allogeneic hematopoietic stem cell transplant and enzyme replacement therapy. Exogenous enzyme therapy appears promising but the benefits may be attenuated, at least in some patients, by the development of an immune response to the delivered enzyme. The incidence and impact of allo-immune responses in these patients remain unknown. Design and MethodsWe developed an immunoglobulin G enzyme-linked immunosorbent assay as well as in vitro catalytic enzyme inhibition and cellular uptake inhibition assays and quantified enzyme inhibition by allo-antibodies. We determined the impact of these antibodies in eight patients who received enzyme therapy before and during hematopoietic stem cell transplantation. In addition, 20 patients who had previously received an allogeneic stem cell transplant were tested to evaluate this treatment as an immune tolerance induction mechanism. ResultsHigh titer immune responses were seen in 87.5% (7/8) patients following exposure to a-Liduronidase. These patients exhibited catalytic enzyme inhibition (5/8), uptake inhibition of catalytically active enzyme (6/8) or both (4/8). High antibody titers generally preceded elevation of previously described biomarkers of disease progression. The median time to development of immune tolerance was 101 days (range, 26-137) after transplantation. All 20 patients, including those with mixed chimerism (22%), tested 1 year after transplantation were tolerized despite normal enzyme levels. ConclusionsWe found a high incidence of neutralizing antibodies in patients with mucopolysaccharidosis type I treated with enzyme replacement therapy. We also found that allogeneic hematopoietic stem cell transplantation was an effective and rapid immune tolerance induction strategy. © F e r r a t a S t o r t i F o u n d a t i o n © F e r r a t a S t o r t i F o u n d a t i o n

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Section: Biomarkers and Chimerism Analysismentioning

confidence: 99%

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

Saif¹,

Bigger²,

Brookes³

et al. 2012

Haematologica

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“…However, it is clear from these publications that adults with severe symptoms of their IEM may have poor outcomes. Importantly, the IEM literature suggests that earlier transplantation results in improved neurologic outcomes in patients with urea cycle defects (McBride (Mazariegos et al 2012), and some lysosomal storage diseases (Wynn et al 2009). Finally, the burden of comorbid disease which may precipitate metabolic decompensation is higher in adults than in children (Summar et al 2005;Lang 2009).…”

Section: Discussionmentioning

confidence: 99%

Barriers to Transplantation in Adults with Inborn Errors of Metabolism

Sirrs¹,

Faghfoury²,

Yoshida³

et al. 2012

JIMD Reports

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“…A simple procedure involves electrophoretic separation of GAGs on polyacrylamide gels, followed by staining of the gels with Alcian Blue. The DS/CS ratio correlates with the level of restored enzyme activity after bone marrow transplantation and ERT suggesting that the ratio is a sensitive measure of biochemical response [8,56]. Direct comparison between the HCII-T biomarker and the DS/CS ratio demonstrated that the two biomarkers generally correlate, with notable exceptions at certain time points [52].…”

Section: Dermatan:chondroitin Sulfate Ratiomentioning

confidence: 97%

Glycan-based biomarkers for the mucopolysaccharidoses

Brown

Lawrence

Langford-Smith

et al. 2011

Molecular Genetics and Metabolism

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The mucopolysaccharidoses (MPS) result from attenuation or loss of enzyme activities required for lysosomal degradation of the glycosaminoglycans, hyaluronan, heparan sulfate, chondroitin/ dermatan sulfate, and keratan sulfate. This review provides a summary of glycan biomarkers that have been used to characterize animal models of MPS, for diagnosis of patients, and for monitoring therapy based on hematopoietic stem cell transplantation and enzyme replacement therapy. Recent advances have focused on the non-reducing terminus of the glycosaminoglycans that accumulate as biomarkers, using a combination of enzymatic digestion with bacterial enzymes followed by quantitative liquid chromatography/mass spectrometry. These new methods provide a simple, rapid diagnostic strategy that can be applied to samples of urine, blood, cerebrospinal fluid, cultured cells and dried blood spots from newborn infants. Analysis of the non-reducing end glycans provides a method for monitoring enzyme replacement and substrate reduction therapies and serves as a discovery tool for uncovering novel biomarkers and new forms of mucopolysaccharidoses.

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Improved Metabolic Correction in Patients with Lysosomal Storage Disease Treated with Hematopoietic Stem Cell Transplant Compared with Enzyme Replacement Therapy

Cited by 129 publications

References 7 publications

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

Hematopoietic stem cell transplantation improves the high incidence of neutralizing allo-antibodies observed in Hurler's syndrome after pharmacological enzyme replacement therapy

Barriers to Transplantation in Adults with Inborn Errors of Metabolism

Glycan-based biomarkers for the mucopolysaccharidoses

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