Gene editing lessened autism symptoms in mice, including obsessive repetitive digging and periodic leaps into the air. Photo courtesy of UT Health Science San Antonio
June 26 (UPI) -- 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."