Stratifying RTT Patients for Clinical Trials A Mutation Based Approach John Christodoulou NSW Centre for Rett Syndrome Research Western Sydney Genetics Program, Children’s Hospital at Westmead Disciplines of Paediatrics & Child Health and Genetic Medicine, University of Sydney AUSTRALIA

“Generic” Therapies potentially of value regardless of the underlying molecular aetiology nutrition seizures scoliosis (development of consensus approach?) breathing irregularities physiotherapy occupational therapy environmental enrichment whole body vibration training?? other…

Environmental Enrichment mouse model studies mice housed in enriched environments with objects of varying textures, sizes, shapes and colours to stimulate enhanced sensory cognitive and motor activity delayed onset and progression of disease in… Huntington model Down syndrome model Alzheimer model Fragile X model Schizophrenia model …and now a RTT model

Promotion of neuronal activation, signalling and plasticity Nithianantharajah and Hannan, Nat Rev Neurosci 2006: 7; 697-709

Mecp2tm1Tam Mice improved motor coordination is lost in heterozygous mice not exposed to an enriched environment BDNF protein levels in 30 week old mice in cerebellum - correction towards normal Kondo et al Eur J Neurosci, in press

Whole Body Vibration Training first developed to enhance muscle strength in athletes increases bone mass in children and adults improves lower limb skin blood flow limited paediatric experience, but is of benefit in: osteogenesis imperfecta cerebral palsy spinal dysraphism worthy of a clinical trial in RTT patients

Individuals with MECP2 Mutations Target the mutation or target the mutation’s consequences…

“Treating” the MECP2 Mutation nonsense mutations – 30% PTC124 penetrates the blood-brain barrier? converting a nonsense to a missense mutation? other mutations novel strategies yet to be developed modifiers? same mutation, variable severity (not just skewed XCI)

What about activating the normal MECP2 allele? a problem of dosage 2 x activity is “toxic” – human and mouse exogenous MeCP2 expression at 112% of normal in the forebrain restores function (Jugloff et al, Hum Molec Genet 2008: 17; 1386-1396) endogenous MeCP2 key brain regions are mosaic for MeCP2 expression in RTT patients (LaSalle et al Hum Molec Genet 2001: 10; 1729-1740) Can high MeCP2 expressing cells exert a positive effect on adjacent low or negatively expressing cells?

MeCP2 target genes as possible substrates for therapeutic intervention Bdnf xHairy2a DLX5 Sgk1 Fkbp5 ID1-3 FXYD1 IGFBP3 Crh UBE3A GABRB3 others…

Conclusions Multi-pronged approach to therapies treatment of specific clinical problems mutation independent correction of the specific mutation modulation of modifiers increase expression of normal MECP2 allele exogenous or endogenous approaches modify the expression of specific MeCP2 target genes

Funding Acknowledgements NHMRC International Rett Syndrome Association Rett Syndrome Research Foundation International Rett Syndrome Foundation Rotary Club of Narellan CWA of NSW Rett Syndrome Australian Research Fund Tissue Resource Centre, Sydney Harvard Brain Bank