Genistein improves neuropathology and. mucopolysaccharidosis type IIIB. Department of Molecular Biology University of Gdansk Poland
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1 Genistein improves neuropathology and corrects behaviour in a mouse model of mucopolysaccharidosis type IIIB Marcelina Malinowska Department of Molecular Biology University of Gdansk Poland
2 MPSIIIB pathology and treatments MPSIIIB is a lysosmal enzyme deficiency resulting in accumulation of undegraded heparan sulphate This results in behavioural problems, progressive neurodegeneration leading to death MPS cells can be cross-corrected corrected by enzyme from the blood or other cells Enzyme is unable to cross the blood brain barrier limiting ERT treatment Haematopoietic stem cell transplants have not shown efficacy Alternative treatments include substrate reduction therapy
3 Genistein as a treatment for MPS IIIB Genistein EGF HO O O EGF receptor OH OH Soy component or can be synthesised Blocks GAG production via tyrosine kinase blockade Piotrowska 26 Eur J Hum Genet Nontoxic, maximum tolerated dose of pure genistein in dogs >5 mg/kg/day McClain 25 Food and chem toxicol 1% crosses blood brain barrier Tsai 25 J chromatogr A Open label trial 5 mg/kg/day -unclear what effect it has in the brain Piotrowska 28 Curr Ther R Clin Exp Activation of transcription factors Doses used mainly 1mg/kg/day Peripheral correction in MPS IIIB mice over 8 weeks Malinowska 29 Mol Genet Metab Proteoglycan (GAG) production Full efficacy trial in mice required
4 Long-term experimental protocol 2 months start 8-1 months behaviour 11 months sacrifice Primary and secondary storage MPS IIIB Bar crossing Brain biochemistry hemicoronal fifths WT Inflammation MPS IIIB 16 mg/kg/day genistein aglycone Open field Brain- histology 8 fields counted Synaptic organisation WT Soy free diet Inverted screen Liver biochemistry and histology Primary storage n=6 per sex
5 Primary storage reduction - Brain MPS IIIB WT LAMP2 low LAMP2 high g rtex LAMP2 stainin % of MPS IIIB co LAMP2 cerebral 31% mpus AMP2 staining PS IIIB hippocam LA % of MP LAMP2 hippocampus 34% x Hep paran sulphate ug/m mg protein Pathological HS brain p=.3 Bar = 1μm 37%
6 Inflammation reduction - Brain MPS IIIB WT GFAP mid Isolectin mid GFAP stain ning No of cells in GFAP cerebral 12% ining ortex Is solectin B4 sta No of cells in co Isolectin B4 cerebral % Bar = 1μm
7 Secondary effects - Brain MPS IIIB WT Control Genistein Control Genistein GM2 VAMP2 high GM2 cerebral Total Gangliosides brain Bar = 1μm VAMP2 cerebral GM2 stainin ng Arbitrary units co ortex p<.5 25% GM3 GM2 GM1 GD1a GD1b GT1b GM2 cerebral Control Genistein MPS IIIB Females MPSIIIB Males WT Males VAMP2 staining bitrary units cor rtex Ar % p=.1 1
8 Open field 1 Distanc ce travelled (m) Distance travelled Behavioural correction Freq quency in centre e No of occurrences in centre m/s) Speed (m Frequency of entering centre Speed in centre Speed over 9 mm/s No of occurrences Speed over 9 mm/s D uration (s) Speed over 9 - frequency Speed over 9 - duration lity Freque ency of immobil No of ocurrences Duration of immobility Time (s) Frequency of immobility p=.1 1 Duration of immobility
9 Conclusions Genistein aglycone effectively reduces pathological heparan sulphate and lysosomal size in the brains of MPS IIIB mice Genistein aglycone reduces neuroinflammation and may improve secondary pathology in the brain; peripheral storage is also reduced Gensitein i aglycone fully corrects most behavioural abnormalities detected t d in MPS IIIB mice at 8 months of age No toxic side effects were observed But - Genistein will not cure MPS IIIB - appears to delay disease progression Doses used to see these effects (16 mg/kg/day) are not achievable with the supplement form of genistein A double blinded placebo controlled clinical trial using high doses of oral genistein aglycone is planned in Manchester in the near future
10 The MPS Stem Cell Research Group MPS Group Ed Wraith Rob Wynn Alex Smith Fiona Wilkinson Kia Langford Angharad O Leary Ana Sergijenko Omar Pathmanaban Jenny Christopher Brian Bigger Materials Science Becky Baldwin Cathy Merry Brett Crawford Jill Brown Jim Beitel U82 Marie Vanier Steven U. Walkley Grzegorz Węgrzyn Genistein work funded by: UK MPS Society, Japanese Society of the Patients and Families with MPS, MPS Schweiz, Gesellschaft fur Mukopolysaccharidosen, Asociacion MPS Espana, Irish Society for Mucopolysaccharide Diseases, Canadian Society for Mucopolysaccharide and Related Diseases, National MPS Society (USA), Swedish MPS Society, Gesellschaft fur MPS e.v., VKS. Supported by the Manchester Biomedical Research Centre Marcelina Malinowska was also supported by the InnoDoktorant scholarships for PhD students from the European Social Found, and by the Program o Introducing of Modern Education Elemnsts at University of Gdansk
11 Inverted Screen Bar Crossing onths ments rted screen 8 mo f rear leg movem Inver No of Inverted sc creen 1 months No of rear leg movements Inverted screen 8 months Inverted screen 1 months Untreated MPSIIIB mice get progressively worse at tasks Genistein treated MPSIIIB mice stabilise or improve ths Bar Crossing 8 mont Score ng 1 months core Bar Crossi S Bar Crossing 8 months Bar Crossing 1 months
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