Researchers reduce autism symptoms in mice using CRISPR
Researchers have used CRISPR-Cas9 gene editing to reduce autism symptoms
in mice with a form of the most common single-gene cause of autism
spectrum disorder, or ASD.
Scientists at the University of California Berkeley developed a method
of editing genes with CRISPR by delivering the DNA-cutting Cas9 enzyme
into the brain, cutting repetitive behavior that is characteristic of
fragile X syndrome. The findings were published Monday in the journal
Nature Biomedical Engineering.
FXS, a common form of ASD, occurs in about 1 in 4,000 males and 1 in 8,000 females.
The researchers used the CRISPR-Gold method they developed to edit the
gene for a neurotransmitter receptor linked to repetitive behaviors, a
common symptom of autism. Based on the study, the researchers think they
may be able to apply the method to other aspects of autism, as well as
other diseases just as Huntington's disease or other polygenic
conditions.
"There are no treatments or cures for autism yet, and many of the
clinical trials of small-molecule treatments targeting proteins that
cause autism have failed," study leader Dr. Hye Young Lee, an assistant
professor of cellular and integrative physiology at the University of
Texas Health Science Center at San Antonio, said in a press release.
"This is the first case where we were able to edit a causal gene for
autism in the brain and show rescue of the behavioral symptoms."
The significant difference in this use of CRISPR, said CRISPR-Gold
inventor Niren Murthy, a UC Berkeley professor of bioengineering, is
that the researchers injected it straight into the brain and it worked.
"This is the first time anyone had ever shown that with non-viral delivery," Murthy said.
Other researchers have inserted genes for Cas9 into neurons via viruses,
but because the gene keeps expressing the Cas9 enzyme other genes are
randomly cut. With CRISPR-Gold, it carries the Cas9 complex itself
directly into cells, makes a few cuts and then disappears.
"If you inject CRISPR DNA using a virus, you can't control how much Cas9
protein and guide RNA are expressed, so injecting it via a virus has a
potential problem," Lee said. "I think the CRISPR-Gold method is very
cool because we can control the amount we wish to inject and that
probably minimizes the side effects of using CRISPR, for example
off-target effects."
For the study, the researchers injected CRISPR-Gold carrying the Cas9
complex into the striatum of mice's brain, a region known to mediate
habit formation -- including repetitive behaviors.
The researchers targeted an excitatory receptor called metabotropic
glutamate receptor 5, or mGluR5, which is involved in communication
between neurons and is known to be dysregulated in FXS.
"Before this experiment, we didn't know if the mGluR5 receptor in the
striatum was specifically involved in exaggerated repetitive behavior;
that is an important biological finding of our study," Lee said.
The researchers say they cut the number of receptor proteins in the mice
by about half, because roughly 50 percent of mGluR5 genes in the
striatum were edited. This resulted in the mice showing 30 percent less
obsessive digging and 70 percent less leaping.
The researchers are now developing CRISPR-Gold particles to be injected
directly into the central nervous system through the spinal cord,
eliminating the need to open the skull and inject them directly into the
brain.
Lee thinks the method can be used to treat conditions that include
opioid addiction, neuropathic pain, schizophrenia and epileptic
seizures, as well as autism, among other conditions.
"CRISPR-Gold can be used to treat a variety of genetic diseases, such as Huntington's disease," Lee said.
"But it's not limited to monogenic diseases; it can also be used against
polygenic diseases, once we figure out the entire network of genes
involved."
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