Lessons from the Mouse: Rett Syndrome is Potentially Treatable

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Lessons from the MouseRett Syndrome is
Potentially Treatable
John Christodoulou NSW Centre for Rett Syndrome
Research Western Sydney Genetics Program,
Childrens Hospital at Westmead Disciplines of
Paediatrics Child Health and Medical Genetics,
University of Sydney
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Testing the motor ability of Mecp2-deficient mice
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Is the brain impairment in Rett syndrome
permanent?

• new research suggests NO!

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Experimental Design
Reversal of Neurological Defects in a Mouse Model
of Rett Syndrome Guy et al. Science, 2007

• created a mouse model where expression of Mecp2
  is blocked
• males have severe neurological abnormalities
  reduced lifespan
• females have less severe neurological
  abnormalities normal survival
• mouse engineered so that Mecp2 expression is
  restored on exposure to a specific drug

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MECP2 Gene Organisation
MBD Methyl Binding Domain TRD Transcription
Repression Domain 3UTR Untranslated Region

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The Stop cassette can be cut out of the gene by a
specific enzyme to restore the Mecp2 gene
allowing it to make the normal Mecp2 protein
again.
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Toxic effect resembled that seen when Mecp2 is
overexpressed in mice.
With reactivation of Mecp2, 9/17 male RTT mice
developed toxicity and died. The rest showed no
toxicity and had normal survival
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Before
12 week old male mouse Note low stance, inertia,
tremor, arrhythmic breathing, and moderate hind
limb clasping. Drug treatment was initiated on
this day.
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After
The same mouse as shown in the previous movie
four weeks later after a course of five weekly
drug injections.
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Female mice with the Stop cassette develop RTT
features _at_ 4 12 months, have a normal lifespan,
and the phenotype appears to stabilise. Often
become obese.
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Female mice that received identical drug
treatment regimes 26 weeks prior to filming.
The first mouse seen is a mutant female that
displayed symptoms at the beginning of the
treatment and is now indistinguishable from
normal. The second mouse entering the frame is a
normal female. The third mouse to appear is a
mutant female not treated. Note inertia and
obesity of this third mouse.
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Summary

• absence of MeCP2 does NOT irreversibly damage
  brain cells
• there is now real hope that a cure for Rett
  syndrome might be possible
• translating this to treatment in humans will be
  the next trick!

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Background
An Emerging Therapy PTC124
Welch et al. Nature 2007 447 87 - 91

• nonsense mutations (in frame UAA, UAG or UGA)
  cause the production of the MeCP2 protein to stop
  dead
• this is called premature termination
• gentamicin prompts ribosomes to read through
  premature termination codons (PTCs)
• but not particularly potent toxic to the kidneys
  and inner ear
• small non-toxic compounds identified through high
  throughput screening that promote PTC read through

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Structural effects of PTC124 on mdx mouse
... and was associated with functional
improvements... - improved muscle strength -
reduced exercise associated muscle damage -
reduced CPK levels (marker of muscle damage)
PTC124 therapy results in the generation of
normal dystrophin protein
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The Potential for PTC124 Therapy

• no obvious toxicity
• relatively frequent type of mutation (5 70)
• Duchenne dystrophy 13 cystic fibrosis
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• Rett syndrome 30
• phase 2 trials in DMD and CF currently under way

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