Previous studies in mice have shown that gene editing may be used to potentially treat conditions such as anxiety. While CRISPR/Cas9 represents a revolutionary gene editing technology, its delivery to the brain is fraught with challenges that current delivery systems do not completely address. A key bottleneck challenge is bypassing the blood–brain barrier. Now, a new study in mice by scientists at Boise State University and Cognigenics demonstrates that a novel CRISPR/Cas9 gene-editing delivery system can bypass the blood–brain barrier and regulate neuronal receptor pathways, to treat chronic anxiety.

The findings are published in PNAS Nexus in an article titled, “Genetic modulation of the HTR2A gene reduces anxiety-related behavior in mice.”

“The expanding field of precision gene editing using CRISPR/Cas9 has demonstrated its potential as a transformative technology in the treatment of various diseases,” the scientists wrote. “However, whether this genome-editing tool could be used to modify neural circuits in the central nervous system (CNS), which are implicated in complex behavioral traits, remains uncertain. In this study, we demonstrate the feasibility of noninvasive, intranasal delivery of adeno-associated virus serotype 9 (AAV9) vectors containing CRISPR/Cas9 cargo within the CNS resulting in modification of the HTR2A receptor gene.”

Troy Rohn, PhD, a professor at Boise State University and colleagues targeted 5HT-2A, a serotonin receptor known to play a role in anxiety and depression. They used a vector based on an inactivated adeno-associated virus to deliver the vector through the nose.

Five weeks after intranasal delivery of the vector and package, 75 mice were tested with standard behavioral assays measuring mouse anxiety. Mice treated with the CRISPR package showed an 8.46-fold reduction in HTR2A expression in their brains, compared with control mice. According to the authors, noninvasive, intranasal delivery of CRISPR/Cas9 therapeutics may help patients who exhibit treatment-resistant anxiety.

“Our findings also demonstrate a significant decrease in anxiety-like behavior in treated mice. This study constitutes the first successful demonstration of a noninvasive CRISPR/Cas9 delivery platform, capable of bypassing the blood–brain barrier and enabling modulation of neuronal 5HT-2A receptor pathways. The results of this study targeting the HTR2A gene provide a foundation for the development of innovative therapeutic strategies for a broad range of neurological disorders, including anxiety, depression, attentional deficits, and cognitive dysfunction,” concluded the scientists.

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