Lessons from the Mouse: Lessons from the Mouse: Rett Syndrome is Rett Syndrome is Potentially Treatable Potentially Treatable John Christodoulou John Christodoulou NSW Centre for Rett Syndrome Research NSW Centre for Rett Syndrome Research Western Sydney Genetics Program, Children’s Hospital at Western Sydney Genetics Program, Children’s Hospital at Westmead Westmead Disciplines of Paediatrics & Child Health and Medical Disciplines of Paediatrics & Child Health and Medical Genetics, Genetics, University of Sydney University of Sydney
17
Embed
Lessons from the Mouse: Rett Syndrome is Potentially Treatable
Lessons from the Mouse: Rett Syndrome is Potentially Treatable. John Christodoulou NSW Centre for Rett Syndrome Research Western Sydney Genetics Program, Children’s Hospital at Westmead Disciplines of Paediatrics & Child Health and Medical Genetics, University of Sydney. - PowerPoint PPT Presentation
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Lessons from the Mouse:Lessons from the Mouse:Rett Syndrome is Potentially Rett Syndrome is Potentially
TreatableTreatable
John ChristodoulouJohn Christodoulou
NSW Centre for Rett Syndrome ResearchNSW Centre for Rett Syndrome Research
Western Sydney Genetics Program, Children’s Hospital at WestmeadWestern Sydney Genetics Program, Children’s Hospital at Westmead
Disciplines of Paediatrics & Child Health and Medical Genetics, Disciplines of Paediatrics & Child Health and Medical Genetics,
University of SydneyUniversity of Sydney
Testing the motor ability of Testing the motor ability of Mecp2-deficient miceMecp2-deficient mice
Is the brain impairment Is the brain impairment
in Rett syndrome in Rett syndrome
permanent?permanent?
new research suggests NO!new research suggests NO!
Experimental DesignExperimental Design• created a mouse model where expression of created a mouse model where expression of
Mecp2Mecp2 is blocked is blocked– males have severe neurological abnormalities & reduced males have severe neurological abnormalities & reduced
lifespanlifespan
– females have less severe neurological abnormalities & normal females have less severe neurological abnormalities & normal survivalsurvival
• mouse engineered so that mouse engineered so that Mecp2Mecp2 expression expression is restored on exposure to a specific drugis restored on exposure to a specific drug
Reversal of Neurological Defects in a Reversal of Neurological Defects in a Mouse Model of Rett SyndromeMouse Model of Rett Syndrome
The The Stop Stop cassette can be cut out of the gene by a cassette can be cut out of the gene by a specific enzyme to restore the specific enzyme to restore the Mecp2Mecp2 gene allowing gene allowing it to make the normal Mecp2 protein again.it to make the normal Mecp2 protein again.
With reactivation of With reactivation of Mecp2, 9/17 maleMecp2, 9/17 male RTT RTT mice developed mice developed toxicity and died.toxicity and died.
The rest showed no The rest showed no toxicity and had toxicity and had normal survivalnormal survival
Toxic effect Toxic effect resembled that seen resembled that seen when Mecp2 is when Mecp2 is overexpressed in overexpressed in mice.mice.
BeforeBefore
12 week old male mouse:12 week old male mouse:Note low stance, inertia, tremor, arrhythmic breathing, and Note low stance, inertia, tremor, arrhythmic breathing, and moderate hind limb clasping. moderate hind limb clasping.
Drug treatment was initiated on this day. Drug treatment was initiated on this day.
The same mouse as shown in the previous movie four The same mouse as shown in the previous movie four weeks later after a course of five weekly drug injections. weeks later after a course of five weekly drug injections.
Female mice with the Female mice with the StopStop cassette develop RTT cassette develop RTT features @ 4 – 12 months, have a normal lifespan, features @ 4 – 12 months, have a normal lifespan, and the phenotype appears to stabilise. Often and the phenotype appears to stabilise. Often become obese.become obese.
Female mice that received identical drug treatment regimes 26 weeks prior to filming. 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 first mouse seen is a mutant female that displayed symptoms at the beginning of the treatment and is now indistinguishable from normal.the treatment and is now indistinguishable from normal.
The second mouse entering the frame is a normal female. 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 The third mouse to appear is a mutant female not treated. Note inertia and obesity of this third mouse. this third mouse.
• absence of MeCP2 does absence of MeCP2 does NOTNOT irreversibly irreversibly damage brain cellsdamage brain cells
• there is now real hope that a cure for Rett there is now real hope that a cure for Rett syndrome might be possiblesyndrome might be possible
• translating this to treatment in humans will translating this to treatment in humans will be the next trick!be the next trick!
BackgroundBackground• nonsense mutations (in frame UAA, UAG or UGA) nonsense mutations (in frame UAA, UAG or UGA)
cause the production of the MeCP2 protein to stop cause the production of the MeCP2 protein to stop deaddead– this is called premature terminationthis is called premature termination
• gentamicin prompts ribosomes to read through gentamicin prompts ribosomes to read through premature termination codons (PTCs)premature termination codons (PTCs)– but not particularly potent; toxic to the kidneys and inner earbut not particularly potent; toxic to the kidneys and inner ear
• small non-toxic compounds identified through high small non-toxic compounds identified through high throughput screening that promote PTC read throughthroughput screening that promote PTC read through
An Emerging Therapy PTC124An Emerging Therapy PTC124Welch et al. Nature 2007: 447; 87 - 91Welch et al. Nature 2007: 447; 87 - 91