New hope for people living with a genetic cause of autism
Research shows gene reactivation can be used to treat Fragile X syndrome


Date:
December 13, 2021
Source:
University of California - Riverside
Summary:
Researchers report they were able to ameliorate Fragile X syndrome
symptoms after inserting the Fmr1 gene into the brains of very
young transgenic mice that had been genetically engineered to lack
this gene.

When the researchers measured brain activity for signs of anxiety
and hyperactivity in response to stimuli such as stresses and
sounds, they found that the reactivation of the gene in these mice
had led them to no longer show Fragile X syndrome symptoms.



FULL STORY ========================================================================== Fragile X syndrome, or FXS, a leading genetic cause of autism, affects
around one in 4,000 males and one in 6,000 females. Its symptoms include increased anxiety, intellectual disability, repetitive behaviors, social communication deficits, and abnormal sensory processing. People living
with FXS generally lack the fragile X mental retardation 1 gene, or Fmr1,
in their brain cells. If their cells have this gene, it is silent and
not producing a protein called FMRP.


========================================================================== Researchers at the University of California, Riverside, report in
the journal Neurobiology of Disease they were able to ameliorate FXS
symptoms after inserting Fmr1 into the brains of very young transgenic
mice that had been genetically engineered to lack this gene. When the researchers measured brain activity for signs of anxiety and hyperactivity
in response to stimuli such as stresses and sounds, they found that the reactivation of the Fmr1 gene in these mice had led them to no longer
show FXS symptoms.

"Our work shows beneficial effects of reactivating the Fmr1 gene, which
would be very welcome news for young children living with FXS," said
Iryna M. Ethell, a professor of biomedical sciences in the UCR School
of Medicine, who led the research.

In their study, Ethell's laboratory, in collaboration with Khaleel
A. Razak, a professor of psychology, selected very young mice -- less
than 3 weeks old - - because brains are most plastic early in life;
the equivalent in humans is around the first 3-5 years.

"For humans, the first 3-5 years are critical in brain development,"
Ethell said. "It's important, therefore, that this early period be
targeted in FXS." The mouse brain, like the human brain, has excitatory
and inhibitory neurons.

Unlike excitatory neurons that lead to a forward propagation of
information, inhibitory neurons work like a brake by suppressing
unnecessary activity and tuning brain activity to specific signals.



========================================================================== Ethell and two colleagues recently published a review article in Nature Neuroscience showing that the dysfunction of inhibitory neurons is a
common pathology in genetic diseases that are linked to autistic spectrum disorders, or ASD.

"In the current study, we targeted excitatory neurons in the second
and third postnatal weeks of the mice to insert the Fmr1 gene," Ethell
said. "Our study shows this period is not too late for manipulating the
brain. We targeted these particular neurons because they establish a
control over inhibitory neurons that are malfunctioning in FXS. At this
time, we do not know if our method would be effective in adults. That
research would be a next step in this line of work." How Ethell and
her team introduced the Fmr1 gene into mouse brain differs from how
the gene would potentially be introduced in a human brain. The final
outcome, however, would be the same, Ethell said. According to her,
CRISPR, a powerful tool for editing genomes, would most likely be used
to reactivate Fmr1 in human brain.

"FXS is most often diagnosed early in a person's life," she said. "We
cannot stress enough, therefore, that the early years are the perfect
time to reactivate the Fmr1 gene. It offers hope that even if this
gene is missing in a child, it can still be introduced, allowing the
child to live a daily life free of FXS. As gene reactivation to treat
FXS receives increasing attention, our results suggest the benefits of
Fmr1 re-expression during the early period of brain plasticity in mice,
which roughly corresponds to the first three years of human life, when
ASD symptoms first emerge in infancy." Next, the research team will
work to restore function in the adult FXS brain.

"The main challenge is that the adult brain is not so plastic," Ethell
said.

"Young brains can do just about anything. But as an adult, have you
tried to learn a new language?" The research was funded by the National Institutes of Health, the Department of Defense, and the FRAXA Research Foundation. First author Maham Rais was also supported by a National
Research Service Award Fellowship from the National Institute of
Neurologic Disorders and Stroke.

Ethell, Razak, and Rais were joined in their study by Jonathan
W. Lovelace, Xinghao S. Shuai, Walker Woodard, Steven Bishay, Leo Estrada, Ashwin R. Sharma, Austin Nguy, Anna Kulinich, Patricia S. Pirbhoy,
Arnold R. Palacios, and David L. Nelson. Except for Nelson, who supplied
the transgenic mice and is at the Baylor College of Medicine in Texas,
all the coauthors are at UCR.

The research paper is titled "Functional consequences of
postnatal interventions in a mouse model of Fragile X syndrome." ========================================================================== Story Source: Materials provided by
University_of_California_-_Riverside. Original written by Iqbal
Pittalwala. Note: Content may be edited for style and length.


========================================================================== Journal References:
1. Maham Rais, Jonathan W. Lovelace, Xinghao S. Shuai, Walker Woodard,
Steven Bishay, Leo Estrada, Ashwin R. Sharma, Austin Nguy, Anna
Kulinich, Patricia S. Pirbhoy, Arnold R. Palacios, David L. Nelson,
Khaleel A.

Razak, Iryna M. Ethell. Functional consequences of postnatal
interventions in a mouse model of Fragile X syndrome. Neurobiology
of Disease, 2022; 162: 105577 DOI: 10.1016/j.nbd.2021.105577
2. Anis Contractor, Iryna M. Ethell, Carlos Portera-Cailliau. Cortical
interneurons in autism. Nature Neuroscience, 2021; 24 (12): 1648
DOI: 10.1038/s41593-021-00967-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211213121750.htm

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