High dose genistein aglycone therapy is safe in patients with mucopolysaccharidoses involving the central nervous system

Genistein (4,5,7-trihydroexyisoflavone), a soy derived isoflavone, has been proposed as a substrate reduction therapy in patients with mucopolysaccharidoses (MPS) disorders with central nervous system involvement based on studies in cultured fibroblasts demonstrating that this agent inhibits glycosaminoglycan synthesis. Several studies have reported treatment of MPS III patients with low dose genistein (5-15 mg/kg/day) with no serious adverse effects and variable neurocognitive outcomes. Mice with MPS IIIB treated with high dose (160 mg/kg/day) genistein exhibited a significant decrease in heparan sulfate accumulation and neuroinflammation in the brain and improvement of the behavioral phenotype. No study to date has been performed using high dose genistein treatment in MPS patients. We initiated an open label study to assess the safety of high dose genistein treatment in MPS patients with neurological impairment. Twenty-two eligible patients were treated at least 12 months with pure synthetic genistein at a dose of 150 mg/kg/day. Safety labs, urine GAG levels, clinical status and history of adverse events were obtained every 3 months and physical examination was performed by single examiner at least every 12 months. While neurocognitive level was not a primary endpoint, participants were asked to obtain annual neurocognitive testing if available and a 9 point disability scale (FPSS) was recorded at each study visit. In the course of 12 months of treatment, we observed no serious adverse events that were unexplained by the underlying condition and no severe adverse events that were felt to be potentially related to the genistein therapy. Two male subjects developed Tanner II breast development not present at baseline which could be related to the mild estrogenic effects of genistein. We observed no consistent decline in urine GAG levels; however, urinary GAG excretion was erratic. After 12 months, the FPSS remained unchanged in 16 patients and declined by 1 point in 2 patients. Based on the results obtained so far, high dose oral genistein therapy appears to be safe in MPS patients and additional testing in a larger randomized placebo controlled trial is needed to further assess safety and efficacy.