There are currently no approved therapies for Sanfilippo disease. The research initiatives that have resulted in clinical trials or are progressing towards clinical trial have one of two objectives; either to boost the enzyme levels or reduce storage (GAGs) through substrate reduction.
Genistein, a substrate reduction therapy, can be purified from soya beans and is recognised as a food supplement. In the pure Genistein the broad spectrum protein, tyrosine kinase inhibitor, blocks GAG production in patient cells from all MPS types tested.; MPS I, MPS II, MPS III, MPS VI and MPS VII. This was published by Piotrowska in 2006 in the European Journal of Genetics.
Mice with MPS IIIB show similar behaviours to children with MPS IIIB, principally hyperactivity. Mice treated with 160mg/kg of pure Genistein were shown to behave very much like normal mice. There was a 30% improvement in Heparan Sulphate in the brain; 12% improvement in the astrocytes; 15% improvement in the microglia and as a consequence behaviour in the MPS IIIB treated mice were fully corrected and neuro inflammation was improved.
There is a good safety data in dogs of up to 500mg/kg as well as in Dr Barbara Burton’s MPS III patient cohort on 150mg/kg study.
The mice data clearly shows a minimum effective dose to treat the brain of 160mg/kg with toxicity at 500mg/kg. Human dosing is normally 1/5th or 1/10th of the mouse dose. However:
The Dutch clinical trial using 10mg/kg a day showed no brain effect despite plasma, GAG and Heparan Sulphate reductions and an aglycone level of 12.
Humans degrade Genistein quicker than mice thus having lower aglycone levels.To achieve an effective dose in the brain in humans the Genistein Clinical trial dose is 160mg/kg.
The Genistein Clinical Trial is taking place at the Manchester Children’s Hospital and is currently recruiting 24 UK patients.
The Clinical Trial is for 1 year duration with 1 year extension and is a phase III, double blinded, randomised, placebo controlled clinical trial of high dose oral Genistein Aglycone in patients with Sanfilippo syndrome (MPSIII A, B and C). The total duration of the clinical trial is 42 months.
The Drug is GMP (Good Manufacturing Practice) grade manufactured by DSM and provided at no cost. If the drug is shown to be effective it can be licenced from this clinical trial.
The clinical trial participants will receive 2 daily doses of 80mg/kg. Adverse events, toxicity and endocrine monitoring will take place. Clinical trial outcome measures will include Urine GAGs and a number of psychological and developmental tests.
Dr Simon Jones
Consultant Metabolic Paediatrician
Manchester Children’s Hospital
Oxford Road, Manchester M13 9WL, UK, Phone: 0161 701 2137/8
For more information please click here.