Gene Editing Tool CRISPR-Gold May Reduce Autism-Related Behaviors, Fragile X Mouse Model Shows

A gene editing tool based on gold nanoparticles called CRISPR-Gold was able to reduce the repetitive behaviors associated with autism spectrum disorders (ASD) in a mouse model of fragile X syndrome (FXS), a recent study shows.

The study, “Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours,” was published in the journal Nature Biomedical Engineering.

Gene therapy holds promise for the treatment of several diseases, including brain disorders, due to its potential to replace or edit specific genes associated with deficiency or overproduction of particular proteins.

To date, gene editing in the brain has mainly relied on viral delivery of the gene editing tool CRISPR-Cas9. However, virus-based systems have drawbacks related to potential immune reactions against it, and continuous production of CRISPR-Cas9-associated molecules, which could lead to toxicity and random editing of other genes, or off-targets.

The recent development of a non-viral CRISPR-Cas9 delivery vehicle — called CRISPR-Gold — by researchers at the University of California, Berkeley, could provide the answer to these problems.

CRISPR-Gold uses gold nanoparticles covered by DNA molecules to carry the CRISPR-Cas9 molecules. This complex is surrounded by a polymer that helps deliver the genetic tool into the appropriate cells. With this system, there is no continuous production of CRISPR-Cas9 molecules, and they work for only a limited period of time before they are degraded.

Researchers at the University of Texas Health Science Center at San Antonio (UTHSCSA), along with colleagues at UC Berkeley, evaluated whether CRISPR-Gold could be used to reduce fragile X-associated repetitive behaviors.

Fragile X syndrome, caused by a mutation in the FMR1 gene, is the most common known single-gene cause of autism spectrum disorders, accounting for about 2.1 percent of patients. A common feature of autism-related disorders is the presence of excessive repetitive behaviors.

An excitatory receptor involved in the communication between nerve cells — called mGluR5 — is known to be abnormally activated not only in fragile X, but also in other autism spectrum disorders. Suppressing mGluR5 in mouse models of autism was found to improve autism-related symptoms — such as social deficits and repetitive behaviors — suggesting high levels of mGluR5 are associated with these behaviors.

This evidence make mGluR5 a potential therapeutic target for autism-related disorders.

Researchers used CRISPR-Gold to delete the gene associated with mGluR5 in a mouse model of fragile X syndrome. The compound was injected directly into the striatum of the brain, a region implicated in habit formation and repetitive behavior.

This approach led to a significant reduction of mGluR5 protein levels in the striatum by 40-50%, and of repetitive behaviors of the mice, such as obsessive digging, by 30%, and increased jumping, by 70%.

The researchers found no signs of CRISPR-Gold-induced immune responses nor of changes in motor activity and weight in treated mice. These findings suggest this is a potentially safe therapy that leads to the specific reduction of autism-related behaviors.

“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,” Hye Young Lee, PhD, the study’s senior author and an assistant professor of cellular and integrative physiology at UTHSCSA, said in a press release.

According to the researchers, this approach could open the door to the rapid development of new brain-targeted therapeutics.

Lee added that these results also provide evidence of the involvement of striatum mGluR5 receptors in the development of excessive repetitive behavior, which until now, was only a theory.

The team is now developing CRISPR-Gold particles that can be delivered to the brain through an injection into the spinal cord (intrathecal injection), avoiding the need to open the skull.

They believe intrathecal injection of CRISPR-Gold could be as effective as the localized injection into the striatum in reducing repetitive behavior, and perhaps even address some of the social interaction problems of autism spectrum disorders, which could potentially improve the lives of affected children and caregivers.