Willink Biochemical Genetics Unit, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester, UK.
Stem Cell and Neurotherapies, Division of Cell Matrix Biology and Regenerative Medicine, University of Manchester, Manchester, UK.
J Inherit Metab Dis. 2021 Sep;44(5):1248-1262. doi: 10.1002/jimd.12407. Epub 2021 Jun 13.
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.
本研究旨在评估高剂量染料木黄酮苷元在黏多糖贮积症 III 型（Sanfilippo 综合征）中的疗效。高剂量的染料木黄酮苷元已被证明可纠正小鼠的神经病理学和过度活跃行为，但在人类中的疗效尚不确定。这是一项单中心、双盲、随机、安慰剂对照研究，具有开放标签扩展阶段。随机参与者接受 160mg/kg/天的染料木黄酮苷元或安慰剂治疗 12 个月；随后所有参与者均接受染料木黄酮苷元治疗 12 个月。主要结局测量指标是脑脊液（CSF）中硫酸乙酰肝素浓度的变化，次要结局测量指标包括血浆和尿液中的硫酸乙酰肝素、尿液中的总糖胺聚糖、认知和适应行为评分、生活质量测量和活动记录仪。21 名参与者被随机分组，20 名参与者完成了安慰剂对照阶段。治疗 12 个月后，染料木黄酮组 CSF 硫酸乙酰肝素浓度降低 5.5%（根据基线值调整），但无统计学意义（P=0.26），并且在开放标签扩展阶段两组的 CSF 硫酸乙酰肝素均增加。染料木黄酮组尿糖胺聚糖的减少明显更大（12 个月后比安慰剂组低 32.1%，P=0.0495）。其他生化和临床参数在两组之间无显著差异。高剂量染料木黄酮苷元（160mg/kg/天）与 CSF 硫酸乙酰肝素的临床意义降低无关，也未发现临床疗效的证据。然而，尿液糖胺聚糖的减少具有统计学意义。这些数据不支持在黏多糖贮积症 III 型中使用染料木黄酮苷元治疗。高剂量染料木黄酮苷元不会导致黏多糖贮积症 III 型的生物标志物有临床意义的减少，也不会改善神经心理学结局。
