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.

Innate Immunity in Mucopolysaccharide Diseases

“…Furthermore, a one-year pilot study proved that oral administration of this molecule results in improved cognitive function in MPS IIIA and IIIB patients [125]. Sadly, the phase III trial in 20 MPSIII patients proved that genistein was ineffectual at reducing GAG content in the brain, and despite modest peripheral reduction in GAG, no neurocognitive benefit was observed [126]. Alternatives that are effective at reducing GAG or GAG sulphation would be of interest.…”

Sanfilippo Syndrome: Optimizing Care with a Multidisciplinary Approach

“…This concerns various types of therapies, including enzyme replacement therapy (provided intrathecally), gene therapy, and substrate reduction therapy. [18][19][20][21] The physical storage of HS inhibits lysosomal functions; however, it is hardly possible to explain all cellular and organismal defects observed in Sanfilippo disease solely by accumulation of this GAG. 2 Nevertheless, if huge amounts of HS cannot be accommodated inside lysosomes, the undegraded molecules can remain in either the cytoplasm, due to a block in further transport to the target organelle, or outside the cell, where GAGs play their major physiological roles.…”

Non-cardiac Manifestations in Adult Patients With Mucopolysaccharidosis

“…No benefit of HSCT on neurocognitive function was noted for MPS III (94), and results are mixed for Bone Marrow Transplantation (BMT) in MPS VII (69,103). Clinical trials of Genistein in MPS III report no change in neuropsychological, behavioral, or quality of life outcomes (95)(96)(97). Preliminary results in MPS IIIA show promise with gene therapy (98).…”