Researchers alleviate symptoms of
Rett syndrome in mice
CAMBRIDGE, Mass. (February 1, 2006) — Rett syndrome
is a debilitating neurological disorder occurring primarily
in girls. While some existing therapies might ease particular
symptoms of the condition, there is no current way to
address the syndrome at a molecular level. Now, researchers
at Whitehead Institute for Biomedical Research, in collaboration
with scientists at Brandeis University, have dramatically
reduced certain manifestations of Rett Syndrome in mice,
marking a clear path in which to explore possible therapies
for people.
"This is the first time we've successfully reduced
the awful symptoms of Rett syndrome using transgenic
techniques," says Whitehead Member Rudolf
Jaenisch, senior author of the paper that will be
published February 2 in the journal Neuron.
"Once we understand the molecular mechanisms of
the disease we may be able to design rational strategies
that may eventually be useful for improving the condition
in people."
Rett syndrome, whose incidence is roughly 1 in 15,000,
is caused by a defective gene on the X chromosome. Most
boys with Rett syndrome die before birth. Girls with
Rett develop normally until about six to eighteen months,
when things begin to go terribly wrong. Their health
deteriorates, and they begin to show symptoms such as
loss of speech, loss of voluntary motor control, constant
hand wringing and seizures.
"Knowing more about the process and about the
precise areas of the brain that are affected will
give us options for exploring future therapies,"
says Whitehead Member Rudolf Jaenisch. |
In March 2001, researchers in the Jaenisch lab published
a paper in Nature Genetics describing how they
had created the first mouse with Rett syndrome by disabling
a gene called MeCP2. Normally, MeCP2 regulates the activities
of other genes, particularly those in the brain. When
it is shut off completely, the mice become lethargic
and a major class of cortical neurons became far less
active—classic symptoms of Rett.
In the fall of 2003, Jaenisch and researchers at Children's
Hospital Boston reported in the journal Science
that MeCP2 interacted with a neuronal gene called Bdnf,
a gene that's highly active in infants age 6 to 18 months-the
same age at which Rett symptoms first appear. But since
this study was conducted using explanted neurons in
a laboratory dish, researchers still had many unanswered
questions about the role of Bdnf in Rett disease progression
in mice.
Qiang Chang, a postdoctoral scientist in the Jaenisch
lab, began to explore this issue by studying the population
of the MeCP2 knock-out mice that Jaenisch had reported
on in 2001. His first finding, gleaned through analyzing
brain tissue, was not altogether unexpected: Mice without
MeCP2 also showed low expression levels of the BDNF
protein. In fact, Chang discovered that when he knocked
out Bdnf altogether in normal mice, symptoms similar
to those observed in the Rett mice occurred. But to
discover whether or not this finding might have therapeutic
relevance, Chang needed to engage in some complex genetic
tinkering.
Chang inserted an additional Bdnf gene into the early
embryos of the MeCP2 knock-out mice. He designed the
gene so that it would be free of all normal regulatory
mechanisms, in effect ensuring that it remains in a
state of constant activity. In other words, while MeCP2
was permanently shut off, the new Bdnf was permanently
switched on, and at maximum capacity.
This time, the findings were striking.
With BDNF hyper-expressed, Chang witnessed a drastic
reduction in certain Rett symptoms. The mice were far
less lethargic, and activity in the cortical neurons
increased. These mice also had slightly larger brains,
a longer lifespan and later onset of disease than the
other Rett mice.
"The next step," says Chang, "is to figure
out exactly why this is happening. Exactly how much
BDNF expression in the mouse brain do you need to achieve
these results, and where does it occur?"
"Knowing more about the process and about the precise
areas of the brain that are affected will give us options
for exploring future therapies," explains Jaenisch,
who is also a professor of biology at MIT.
"We're encouraged by these results," says
Monica Coenraads, co-founder and director of research
for Rett Syndrome Research Foundation, who helped support
this work. "Should this prove to be therapeutically
relevant, we look forward to participating in the transition
from lab to clinic."
This research was supported by the Rett Syndrome Research
Foundation, a McKnight Foundation grant and the National
Cancer Institute.
|
