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The
following paper was released by the online journal Science
Express at 2pm on February 8, 2007:
Reversal
of Neurological Defects in a Mouse Model of Rett Syndrome
Jacky
Guy, Jian Gan, Jim Selfridge, Stuart Cobb, Adrian Bird
Acknowledgement:
This research was funded by grants from Wellcome Trust,
Rett Syndrome Research Foundation and Rett Syndrome
UK/Jeans for Genes
The
Experiment:
The laboratory of Dr. Adrian Bird at the University
of Edinburgh, Scotland, genetically modified mice so
that production of MeCP2 could be stopped for a period
of time and then allowed to be produced and serve its
normal function. This created the equivalent of a “temporary”
mutation. The question was if the “temporary mutation”
was in place long enough for all the mouse symptoms
of Rett Syndrome to appear and run their course, would
it then be too late to reverse symptoms and improve
the disorder when normal MeCP2 function was restored.
The
Study:
The technology used in this study is called Cre-lox.
The method provides a way of locking and then unlocking
a gene. Mice were genetically modified to keep MECP2
silenced by inserting a foreign piece of DNA called
a lox Stop cassette, thereby creating a model of the
deficits seen in Rett.Syndrome. The lox Stop cassette
could be spliced out, at will, by using a protein called
Cre. Cre was kept anchored to an estrogen receptor in
the cytoplasm of the cell while the mice, deprived of
functioning MECP2, developed the Rett Syndrome symptoms.
Symptomatic mice were then treated with a drug to release
the Cre, which migrates to the nucleus and splices out
the lox Stop cassette, unlocking MECP2 and allowing
it to function normally. In this genetic manipulation,
the normal gene is already present in the mouse model
but is under the control of tamoxifen, an estrogen analogue,
and is only activated by dosing with tamoxifen.
The
Results:
Turning off MeCP2 resulted in mice that had the full
mouse symptoms of Rett syndrome (most but not all match
human symptoms). When MeCP2 was gradually turned on
in these mice, Rett syndrome symptoms were reversed
even in mature mice where symptoms has been allowed
to progress and some mice were days from dying. Long
term potentiation (LTP), a cellular basis of learning
and memory, is defective in mouse models of Rett syndrome.
In this study LTP was defective when MeCP2 was locked
and LTP was then restored to its normal function by
the reversal experiments.
The
Conclusions:
This paper shows that while Rett syndrome has a neurodevelopmental
component, it should not be considered a strictly neurodevelopmental
disorder with a point of no return. The key finding
is a proof of concept. The neurological abnormalities
in mouse models of Rett syndrome are reversible, even
after they are already evident. The exciting implication
this suggests is that in humans treatment does not need
to begin at birth or before the onset of typical features
of Rett syndrome. While the genetic manipulation used
in this study is not applicable to human treatments,
it opens the door to the development of new therapeutic
approaches.
Cautionary
Notes: The authors' conclusion suggests no direct
therapeutic intervention in humans. Two cautionary notes
are mentioned. One is that aggressive activation of
the gene in male mice lacking any MeCP2 expression resulted
in death of 9 of 17 animals. The remaining animals showed
a return to 'normalcy'. Thus, the effect of aggressive
gene activation is all or none. The authors also acknowledge
that studying the males is not the most proper approach
– or, as stated in the paper, female mice with
some cells already expressing the normal gene 'may be
the most appropriate model' to study RS in humans. It
appears that activation of the normal gene in these
females was accomplished more slowly and did not produce
the all or none phenomenon noted in the males.
To
read the full paper, click here: www.rettsyndrome.org.
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