High dose genistein in Sanfilippo syndrome: A randomised controlled trial

Arunabha Ghosh; Stewart Rust; Kia Langford-Smith; Daniel Weisberg; Maria Canal; Catherine Breen; Michelle Hepburn; Karen Tylee; Frédéric M. Vaz; Andy Vail; Frits Wijburg; Claire O'Leary; Helen Parker; J. Ed Wraith; Brian W. Bigger; Simon A. Jones

doi:https://doi.org/10.1002/jimd.12407

High dose genistein in Sanfilippo syndrome: A randomised controlled trial

Arunabha Ghosh, Stewart Rust, Kia Langford-Smith, Daniel Weisberg, Maria Canal, Catherine Breen, Michelle Hepburn, Karen Tylee, Frédéric M. Vaz, Andy Vail, Frits Wijburg, Claire O'Leary, Helen Parker, J. Ed Wraith, Brian W. Bigger, Simon A. Jones

Research output: Contribution to journal › Article › Academic › peer-review

24 Citations (Scopus)

Abstract

The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double-blinded, randomised, placebo-controlled study with open-label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty-one participants were randomised and 20 completed the placebo-controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P =.26), and CSF heparan sulfate increased in both groups during the open-label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P =.0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III.

Original language	English
Pages (from-to)	1248-1262
Number of pages	15
Journal	Journal of Inherited Metabolic Disease
Volume	44
Issue number	5
Early online date	2021
DOIs	https://doi.org/10.1002/jimd.12407
Publication status	Published - Sept 2021

Keywords

Sanfilippo
genistein
lysosomal storage disorders
mucopolysaccharidosis
substrate reduction therapy

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https://doi.org/10.1002/jimd.12407

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Ghosh, A., Rust, S., Langford-Smith, K., Weisberg, D., Canal, M., Breen, C., Hepburn, M., Tylee, K., Vaz, F. M., Vail, A., Wijburg, F., O'Leary, C., Parker, H., Wraith, J. E., Bigger, B. W., & Jones, S. A. (2021). High dose genistein in Sanfilippo syndrome: A randomised controlled trial. Journal of Inherited Metabolic Disease, 44(5), 1248-1262. https://doi.org/10.1002/jimd.12407

@article{1b633927f1f6468aaaf14c197bd9ed6c,

title = "High dose genistein in Sanfilippo syndrome: A randomised controlled trial",

abstract = "The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double-blinded, randomised, placebo-controlled study with open-label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty-one participants were randomised and 20 completed the placebo-controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P =.26), and CSF heparan sulfate increased in both groups during the open-label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P =.0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III.",

keywords = "Sanfilippo, genistein, lysosomal storage disorders, mucopolysaccharidosis, substrate reduction therapy",

author = "Arunabha Ghosh and Stewart Rust and Kia Langford-Smith and Daniel Weisberg and Maria Canal and Catherine Breen and Michelle Hepburn and Karen Tylee and Vaz, {Fr{\'e}d{\'e}ric M.} and Andy Vail and Frits Wijburg and Claire O'Leary and Helen Parker and Wraith, {J. Ed} and Bigger, {Brian W.} and Jones, {Simon A.}",

note = "Funding Information: We thank DSM Nutritional Products Ltd and in particular Dr Kevin Prudence for providing GMP Bonistein free of charge and to Dr Jerome Ravot for providing analytics for stability testing free of charge on the trial. Jamie Farrar at Quay Pharma ensured that GCP and GMP repackaging ran smoothly. We thank Dr George Georgiou at MFT R&D, and Laura Crowther who both provided valuable input to the CTA and regulatory submission for this academic clinical trial. We thank the nursing and administrative team at the Wellcome Trust Children's Clinical Research Facility at Royal Manchester Children's Hospital (RMCH) who undertook the day to day running of the study. We thank Carolyn Davies in RMCH pharmacy who was responsible for management of the investigational medical product and randomisation procedures. The Chief Investigator was Dr Simon Jones and the Chief Scientific Investigator Prof. Brian Bigger. The study was funded by a clinical trial grant to B.B., S.J. and J.E.W. from the UK MPS society. This was made up of individual contributions from the following societies: Spanish MPS Society, German MPS Society, Swiss MPS Society, Irish MPS Society, New Zealand MPS Society, Japanese MPS Society, Austrian MPS Society, Hong Kong MPS Society, French MPS Society, National MPS Society USA, Norah Al Ballah Foundation, Sanfilippo Children's Research Foundation, Canadian Society for Mucopolysaccharide and Related Diseases, Swedish MPS Society, Gesellschaft fur MPS e.V., VKS, Shields Cycle. The study was also independently funded by the GEM Appeal, and the National MPS society. The work was supported by the Manchester Biomedical Research Centre and the Wellcome Trust Children's Clinical Research Centre. Funding Information: We thank DSM Nutritional Products Ltd and in particular Dr Kevin Prudence for providing GMP Bonistein free of charge and to Dr Jerome Ravot for providing analytics for stability testing free of charge on the trial. Jamie Farrar at Quay Pharma ensured that GCP and GMP repackaging ran smoothly. We thank Dr George Georgiou at MFT R&D, and Laura Crowther who both provided valuable input to the CTA and regulatory submission for this academic clinical trial. We thank the nursing and administrative team at the Wellcome Trust Children's Clinical Research Facility at Royal Manchester Children's Hospital (RMCH) who undertook the day to day running of the study. We thank Carolyn Davies in RMCH pharmacy who was responsible for management of the investigational medical product and randomisation procedures. The Chief Investigator was Dr Simon Jones and the Chief Scientific Investigator Prof. Brian Bigger. The study was funded by a clinical trial grant to B.B., S.J. and J.E.W. from the UK MPS society. This was made up of individual contributions from the following societies: Spanish MPS Society, German MPS Society, Swiss MPS Society, Irish MPS Society, New Zealand MPS Society, Japanese MPS Society, Austrian MPS Society, Hong Kong MPS Society, French MPS Society, National MPS Society USA, Norah Al Ballah Foundation, Sanfilippo Children's Research Foundation, Canadian Society for Mucopolysaccharide and Related Diseases, Swedish MPS Society, Gesellschaft fur MPS e.V., VKS, Shields Cycle. The study was also independently funded by the GEM Appeal, and the National MPS society. The work was supported by the Manchester Biomedical Research Centre and the Wellcome Trust Children's Clinical Research Centre. Funding Information: A.G. declares travel grant from Biomarin, unrelated to the submitted work; S.R. declares travel grants and speaker fees from Takeda, Vitaflo, unrelated to the submitted work; K.L. has no conflicts to declare; D.W. has no conflicts to declare; M.C. has no conflicts to declare; C.B. has no conflicts to declare; M.H. has no conflicts to declare; K.T. has no conflicts to declare; F.V. has no conflicts to declare; A.V. has no conflicts to declare; F.W. has no conflicts to declare; C.O. has no conflicts to declare. H.P. has no conflicts to declare; J.E.W. N/A; B.B. declares being an S.A.B member and shareholder of Orchard Therapeutics and the recipient of unrestricted clinical trial grants from Orchard Therapeutics and Avrobio ‐unrelated to the submitted work; S.J. declares being investigator, SAB member and stockholder of Orchard therapeutics, and investigator and consultant for Takeda (formally Shire HGT), unrelated to the submitted work. Publisher Copyright: {\textcopyright} 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = sep,

doi = "https://doi.org/10.1002/jimd.12407",

language = "English",

volume = "44",

pages = "1248--1262",

journal = "Journal of Inherited Metabolic Disease",

issn = "0141-8955",

publisher = "Springer Netherlands",

number = "5",

}

TY - JOUR

T1 - High dose genistein in Sanfilippo syndrome: A randomised controlled trial

AU - Ghosh, Arunabha

AU - Rust, Stewart

AU - Langford-Smith, Kia

AU - Weisberg, Daniel

AU - Canal, Maria

AU - Breen, Catherine

AU - Hepburn, Michelle

AU - Tylee, Karen

AU - Vaz, Frédéric M.

AU - Vail, Andy

AU - Wijburg, Frits

AU - O'Leary, Claire

AU - Parker, Helen

AU - Wraith, J. Ed

AU - Bigger, Brian W.

AU - Jones, Simon A.

N1 - Funding Information: We thank DSM Nutritional Products Ltd and in particular Dr Kevin Prudence for providing GMP Bonistein free of charge and to Dr Jerome Ravot for providing analytics for stability testing free of charge on the trial. Jamie Farrar at Quay Pharma ensured that GCP and GMP repackaging ran smoothly. We thank Dr George Georgiou at MFT R&D, and Laura Crowther who both provided valuable input to the CTA and regulatory submission for this academic clinical trial. We thank the nursing and administrative team at the Wellcome Trust Children's Clinical Research Facility at Royal Manchester Children's Hospital (RMCH) who undertook the day to day running of the study. We thank Carolyn Davies in RMCH pharmacy who was responsible for management of the investigational medical product and randomisation procedures. The Chief Investigator was Dr Simon Jones and the Chief Scientific Investigator Prof. Brian Bigger. The study was funded by a clinical trial grant to B.B., S.J. and J.E.W. from the UK MPS society. This was made up of individual contributions from the following societies: Spanish MPS Society, German MPS Society, Swiss MPS Society, Irish MPS Society, New Zealand MPS Society, Japanese MPS Society, Austrian MPS Society, Hong Kong MPS Society, French MPS Society, National MPS Society USA, Norah Al Ballah Foundation, Sanfilippo Children's Research Foundation, Canadian Society for Mucopolysaccharide and Related Diseases, Swedish MPS Society, Gesellschaft fur MPS e.V., VKS, Shields Cycle. The study was also independently funded by the GEM Appeal, and the National MPS society. The work was supported by the Manchester Biomedical Research Centre and the Wellcome Trust Children's Clinical Research Centre. Funding Information: We thank DSM Nutritional Products Ltd and in particular Dr Kevin Prudence for providing GMP Bonistein free of charge and to Dr Jerome Ravot for providing analytics for stability testing free of charge on the trial. Jamie Farrar at Quay Pharma ensured that GCP and GMP repackaging ran smoothly. We thank Dr George Georgiou at MFT R&D, and Laura Crowther who both provided valuable input to the CTA and regulatory submission for this academic clinical trial. We thank the nursing and administrative team at the Wellcome Trust Children's Clinical Research Facility at Royal Manchester Children's Hospital (RMCH) who undertook the day to day running of the study. We thank Carolyn Davies in RMCH pharmacy who was responsible for management of the investigational medical product and randomisation procedures. The Chief Investigator was Dr Simon Jones and the Chief Scientific Investigator Prof. Brian Bigger. The study was funded by a clinical trial grant to B.B., S.J. and J.E.W. from the UK MPS society. This was made up of individual contributions from the following societies: Spanish MPS Society, German MPS Society, Swiss MPS Society, Irish MPS Society, New Zealand MPS Society, Japanese MPS Society, Austrian MPS Society, Hong Kong MPS Society, French MPS Society, National MPS Society USA, Norah Al Ballah Foundation, Sanfilippo Children's Research Foundation, Canadian Society for Mucopolysaccharide and Related Diseases, Swedish MPS Society, Gesellschaft fur MPS e.V., VKS, Shields Cycle. The study was also independently funded by the GEM Appeal, and the National MPS society. The work was supported by the Manchester Biomedical Research Centre and the Wellcome Trust Children's Clinical Research Centre. Funding Information: A.G. declares travel grant from Biomarin, unrelated to the submitted work; S.R. declares travel grants and speaker fees from Takeda, Vitaflo, unrelated to the submitted work; K.L. has no conflicts to declare; D.W. has no conflicts to declare; M.C. has no conflicts to declare; C.B. has no conflicts to declare; M.H. has no conflicts to declare; K.T. has no conflicts to declare; F.V. has no conflicts to declare; A.V. has no conflicts to declare; F.W. has no conflicts to declare; C.O. has no conflicts to declare. H.P. has no conflicts to declare; J.E.W. N/A; B.B. declares being an S.A.B member and shareholder of Orchard Therapeutics and the recipient of unrestricted clinical trial grants from Orchard Therapeutics and Avrobio ‐unrelated to the submitted work; S.J. declares being investigator, SAB member and stockholder of Orchard therapeutics, and investigator and consultant for Takeda (formally Shire HGT), unrelated to the submitted work. Publisher Copyright: © 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9

Y1 - 2021/9

N2 - The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double-blinded, randomised, placebo-controlled study with open-label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty-one participants were randomised and 20 completed the placebo-controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P =.26), and CSF heparan sulfate increased in both groups during the open-label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P =.0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III.

AB - The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double-blinded, randomised, placebo-controlled study with open-label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty-one participants were randomised and 20 completed the placebo-controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P =.26), and CSF heparan sulfate increased in both groups during the open-label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P =.0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III.

KW - Sanfilippo

KW - genistein

KW - lysosomal storage disorders

KW - mucopolysaccharidosis

KW - substrate reduction therapy

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U2 - https://doi.org/10.1002/jimd.12407

DO - https://doi.org/10.1002/jimd.12407

M3 - Article

C2 - 34047372

SN - 0141-8955

VL - 44

SP - 1248

EP - 1262

JO - Journal of Inherited Metabolic Disease

JF - Journal of Inherited Metabolic Disease

IS - 5

ER -

High dose genistein in Sanfilippo syndrome: A randomised controlled trial

Abstract

Keywords

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