1. 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

2. “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…

3. 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

4. Promotion of neuronal activation,
signalling and plasticity
Nithianantharajah and Hannan, Nat Rev Neurosci 2006: 7;

5. 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

6. 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

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

8. “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)

9. 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; )
endogenous MeCP2
key brain regions are mosaic for MeCP2 expression in RTT patients (LaSalle et al Hum Molec Genet 2001: 10; )
Can high MeCP2 expressing cells exert a positive effect on adjacent low or negatively expressing cells?

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

11. 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

12. 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