Genistein in Sanfilippo disease: A randomized controlled crossover trial

Ruijter, Jessica de; Valstar, Marlies J.; Narajczyk, Magdalena; Węgrzyn, Grzegorz; Kulik, Wim; IJlst, Lodewijk; Wagemans, Tom; Wal, Willem M. van der; Wijburg, Frits A.

doi:10.1002/ana.22643

Cited by 106 publications

(74 citation statements)

References 33 publications

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“…Two other studies with MPS III patients indicated that some disease-linked parameters and symptoms (like hair morphology and urinary GAG level) could be improved during GET IT (Malinova et al 2012), while changes in other parameters (like a disability score) were not observed (Delgadillo et al 2011). Nevertheless, results of very recent double-blinded placebo-controlled clinical trial, which evaluated efficacy of GET IT for MPS III, indicated that despite the fact that a statistically significant decrease in GAG levels in urine and plasma was found when genistein was administered at the dose of 10 mg/kg/day, no statistically significant clinical improvement could be observed during 6-month treatment (de Ruijter et al 2012). Therefore, it was suspected that higher doses of genistein might be considerably more efficacious (Wegrzyn 2012), especially since the most positive effects were reported in mice at genistein dose of 160 mg/kg/ day (Malinowska et al 2010), which is more than 10 times higher than the highest dose used to date in published human studies (Malinova et al 2012).…”

Section: Efficacy Of Srt In In Vitro Studies Experiments With Animalmentioning

confidence: 99%

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Banecka-Majkutewicz

Jakóbkiewicz‐Banecka

Gabig-Cimińska

et al. 2012

Arch. Immunol. Ther. Exp.

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Mucopolysaccharidoses (MPS) are inherited metabolic diseases caused by mutations in genes coding for lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Dysfunction of any of these enzymes results in the accumulation of GAGs, which leads to severe clinical symptoms and significantly shortened life span. Several kinds of therapies have been proposed to treat MPS, including bone marrow or stem cell transplantation, enzyme replacement therapy, and gene therapy. Another option is substrate reduction therapy (SRT), in which synthesis of GAGs is inhibited. Recent studies employing in vitro and animal models suggested that this therapy may be efficient in decreasing levels of GAGs in MPS cells, including those bearing two null alleles of the affected gene. Results of behavioral tests in animals as well as some preliminary clinical observations with pediatric patients corroborated the suggestions about possible efficacy of SRT in MPS treatment, including brain functions. Efficient reduction of GAG levels in MPS cells homozygous for null mutations may be intriguing in the commonly accepted scheme of SRT mode of action. In this paper, we propose an explanation of this phenomenon, based on already known facts. Thus, we suggest that SRT may lead to reduction of GAG levels in MPS cells due to inhibition of efficiency of GAG synthesis combined with (a) any readthrough of the stop codon, (b) dilution of already accumulated GAGs due to cell growth followed by cell divisions, and (c) action of endoglycosidases degrading GAGs, e.g., heparanase, in combination with functional GAG-specific hydrolases.

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Section: Efficacy Of Srt In In Vitro Studies Experiments With Animalmentioning

confidence: 99%

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Banecka-Majkutewicz

Jakóbkiewicz‐Banecka

Gabig-Cimińska

et al. 2012

Arch. Immunol. Ther. Exp.

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“…After digestion, the samples are loaded into the LC-MS/MS for quantitation, and the results are compared with control samples (Figure 2). The LC-MS/MS method for analysis of disaccharides not only shows sensitivity and specificity for detecting all subtypes of MPS but also can monitor therapeutic efficacy in MPS patients and animal models [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. This method has an advantage of being both GAG-specific and quantitative.…”

Section: History Of Gag Assay By Tandem Mass Spectrometry (Ms/ms)mentioning

confidence: 99%

“…Total urinary GAG, a potential biomarker for MPS, is measured spectrometrically by using DMB [17,18,33,34] or Alcian blue [23,35]; however, these methods cannot be applied to blood without protease treatment, since protein in the specimen hinders the binding of the dye to the GAG. Moreover, the dye itself tends to decompose, leading to a high background and false positive results.…”

Section: Introductionmentioning

confidence: 99%

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

Tomatsu

Shimada

Mason

et al. 2015

Molecular Genetics and Metabolism

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Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by deficiency of the lysosomal enzymes essential for catabolism of glycosaminoglycans (GAGs). Accumulation of undegraded GAGs results in dysfunction of multiple organs, resulting in distinct clinical manifestations. A range of methods have been developed to measure specific GAGs in various human samples to investigate diagnosis, prognosis, pathogenesis, GAG interaction with other molecules, and monitoring therapeutic efficacy. We OPEN ACCESSMetabolites 2014, 4 656 established ELISA, liquid chromatography tandem mass spectrometry (LC-MS/MS), and an automated high-throughput mass spectrometry (HT-MS/MS) system (RapidFire) to identify epitopes (ELISA) or disaccharides (MS/MS) derived from different GAGs (dermatan sulfate, heparan sulfate, keratan sulfate, and/or chondroitin sulfate). These methods have a high sensitivity and specificity in GAG analysis, applicable to the analysis of blood, urine, tissues, and cells. ELISA is feasible, sensitive, and reproducible with the standard equipment. HT-MS/MS yields higher throughput than conventional LC-MS/MS-based methods while the HT-MS/MS system does not have a chromatographic step and cannot distinguish GAGs with identical molecular weights, leading to a limitation of measurements for some specific GAGs. Here we review the advantages and disadvantages of these methods for measuring GAG levels in biological specimens. We also describe an unexpected secondary elevation of keratan sulfate in patients with MPS that is an indirect consequence of disruption of catabolism of other GAGs.

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“…Finally, Gen has been recently proposed as therapy for Sanfilippo disease. In combination with an anti-CD19, it was also found to be an active agent for the control of leukemic human B lymphocytes [8].…”

Section: Introductionmentioning

confidence: 98%

Isoflavone aglycons-sulfobutyl ether-β-cyclodextrin inclusion complexes: in solution and solid state studies

Stancanelli

Venuti

Arigò

et al. 2015

J Incl Phenom Macrocycl Chem

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The effect of a polyanionic variably substituted sulfobutyl ether-b-cyclodextrin (SBE-b-CyD), complexation on the UV absorption of genistein (Gen) and daidzein (Dai) was studied in pure water. A phase solubility study was performed, according to the method reported by Higuchi and Connors, to evaluate the changes of isoflavones in the complexation state and type-A L solubility diagrams for both isoflavones were obtained suggesting that they form complexes with 1:1 molar ratio. These results were confirmed by Job's plot method. Complexation strongly increases the water solubility of isoflavones. The in vitro dissolution of isoflavones entrapped into SBE-b-CyD significantly surpassed that of the free isoflavones (over 90 % of the loaded Gen and Dai dissolved in 15 and 30 min, respectively). Finally, 1:1 molar ratio solid complexes were prepared by the kneading method and characterized in solid state by FTIR-ATR spectroscopy, with particular regard to O-H and C=O stretching vibrations, achieving structural information on the modifications induced by complexation on the H-bond scheme, also by applying band decomposition and curve-fit.

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Genistein in Sanfilippo disease: A randomized controlled crossover trial

Cited by 106 publications

References 33 publications

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

Isoflavone aglycons-sulfobutyl ether-β-cyclodextrin inclusion complexes: in solution and solid state studies

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