Improvement in the range of joint motion in seven patients with mucopolysaccharidosis type II during experimental gene expression‐targeted isoflavone therapy (GET IT)

Marucha, Jolanta; Tylki‐Szymańska, Anna; Jakóbkiewicz‐Banecka, Joanna; Piotrowska, Ewa; Kłoska, Anna; Czartoryska, Barbara; Węgrzyn, Grzegorz

doi:10.1002/ajmg.a.34146

Cited by 47 publications

(35 citation statements)

References 27 publications

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“…Since it slows down the production of glycosphingolipids, it should be effective in reducing storage of these compounds. Although positive effects of such treatment in clinical trials were reported (Elstein et al 2004;Pastores et al 2005), its efficacy in Gaucher disease has recently been questioned (Tylki-Szymanska et al 2011;Machaczka et al 2012).…”

Section: Substrate Reduction Therapies (Srps) For Mpsmentioning

confidence: 99%

“…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). On the other hand, recent clinical report indicated that not only MPS III but also MPS II patients may potentially benefit from GET IT as a special kind of SRT (Marucha et al 2011). An important finding is a lack of adverse effects in all the studies on SRT for MPS reported to date and cited above.…”

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

confidence: 99%

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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: Substrate Reduction Therapies (Srps) For Mpsmentioning

confidence: 99%

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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“…In all studies on experimental GET IT for MPS patients published to date, a genistein-rich isoflavone extract was used with the genistein dose of 5 mg/kg/day Delgadillo et al 2011;Marucha et al 2011). However, authors of the most recent studies suggested that an increase in the genistein dose might result in higher efficacy of GET IT (Delgadillo et al 2011;Piotrowska et al 2011).…”

Section: Introductionmentioning

confidence: 97%

“…Then, a 2-year follow-up study was performed, indicating that at this particular dose of genistein, after the initial improvement, the patients' state stabilized (in some patients) or slowly deteriorated (in other patients) . Another recent study showed that GET IT may be useful in treatment of patients suffering from MPS II (Hunter disease), another type of MPS in which a large fraction of patients suffers from deterioration of brain functions (Marucha et al 2011).…”

Section: Introductionmentioning

confidence: 99%

The Use of Elevated Doses of Genistein-Rich Soy Extract in the Gene Expression-Targeted Isoflavone Therapy for Sanfilippo Disease Patients

2011

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Mucopolysaccharidoses (MPS) are severe, inherited metabolic disorders caused by storage of glycosaminoglycans (GAGs). Sanfilippo disease (mucopolysaccharidosis type III, MPS III) is described as severe neurological type of MPS, characterized by rapid deterioration of brain functions. No therapy for Sanfilippo disease is approved to date, however, a specific substrate reduction therapy (SRT), called gene expression-targeted isoflavone therapy (GET IT), has been used as an experimental therapy. In this report, we describe effects of treatment of six Sanfilippo disease patients with GET IT, in which the dose of genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one), an active compound of GET IT present in the soy isoflavone extract, has been increased to 10, and then to 15 mg/kg/day, contrary to the previously reported dose of 5 mg/kg/day. By measuring levels of urinary GAGs and assessing hair dysmorphology as biomarkers, and by considering clinical symptoms of patients, we obtained results suggesting that elevated doses of genistein may improve efficacy of GET IT for Sanfilippo disease.

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“…Although genistein appears to be well tolerated in high doses, adverse effects, which are associated with its potential antiproliferative and estrogenic actions, have been reported and may include hepatotoxicity and hormonal disbalance (Kim et al 2013;Singh et al 2014). The only study on the effects of genistein on MPSrelated bone disease showed increased range of joint motion in genistein-treated MPS II patients, suggesting that genistein at least reaches the surrounding connective and muscle tissue of the joints (Marucha et al 2011). Because genistein can reach the bone tissue (Coldham and Sauer 2000), we fed MPS I mice a high-dose genistein diet to evaluate its potential for the treatment of MPS I-related bone disease.…”

Section: Introductionmentioning

confidence: 99%

Adverse Effects of Genistein in a Mucopolysaccharidosis Type I Mouse Model

et al. 2015

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Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder characterized by diminished degradation of the glycosaminoglycans heparan sulfate (HS) and dermatan sulfate (DS). Patients present with a variety of symptoms, including severe skeletal disease. Current therapeutic strategies have only limited effects on bone disease. The isoflavone genistein has been studied as a potential therapy for the mucopolysaccharidoses because of its putative ability to inhibit GAG synthesis and subsequent accumulation. Cell, animal, and clinical studies, however, showed variable outcomes. To determine the effects of genistein on MPS I-related bone disease, wild-type (WT) and MPS I mice were fed a genistein-supplemented diet (corresponding to a dose of approximately 160 mg/kg/day) for 8 weeks. HS and DS levels in bone and plasma remained unchanged after genistein supplementation, while liver HS levels were decreased in genistein-fed MPS I mice as compared to untreated MPS I mice. Unexpectedly, genistein-fed mice exhibited significantly decreased body length and femur length. In addition, 60% of genistein-fed MPS I mice developed a scrotal hernia and/or scrotal hydrocele, manifestations ,which were absent in WT or untreated MPS I mice. In contrast to studies in MPS III mice, our study in MPS I mice demonstraes no beneficial but even potential adverse effects of genistein supplementation. Our results urge for a cautious approach on the use of genistein, at least in patients with MPS I.

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Improvement in the range of joint motion in seven patients with mucopolysaccharidosis type II during experimental gene expression‐targeted isoflavone therapy (GET IT)

Cited by 47 publications

References 27 publications

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

Putative Biological Mechanisms of Efficiency of Substrate Reduction Therapies for Mucopolysaccharidoses

The Use of Elevated Doses of Genistein-Rich Soy Extract in the Gene Expression-Targeted Isoflavone Therapy for Sanfilippo Disease Patients

Adverse Effects of Genistein in a Mucopolysaccharidosis Type I Mouse Model

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