New non-invasive CRISPR technique eliminates anxiety in mice

The breakthrough could be a game changer for those resistant to the current commonly administered medications.
Loukia Papadopoulos
Mouse standing on a branch with black background
New CRISPR technique eliminates anxiety in mice

Nick Fewings /Unsplash  

Anyone who has ever experienced anxiety knows firsthand how debilitating it can be. It’s also quite common.

According to the World Health Organization (WHO), in 2019, 301 million people around the globe were living with an anxiety disorder, including 58 million children and adolescents.

Now, researchers may have found a non-invasive and effective cure – as tested in mouse models. The details of the new CRISPR method were outlined in a news release by PNAS NEXUS published on Tuesday.

What the researchers did

“A study in mice reports a CRISPR/Cas9 gene-editing delivery system, capable of bypassing the blood-brain-barrier and modulating neuronal receptor pathways, to treat chronic anxiety. Troy Rohn and colleagues targeted 5HT-2A, a serotonin receptor known to play a role in anxiety and depression. The authors used a vector based on an inactivated adeno-associated virus to deliver the vector through the nose. The vector delivers a guide RNA to neurons,” said the statement.

“The guide RNA binds to the target receptor gene, HTR2A, which is then cut at a specific location by the enzyme Cas9. Five weeks after intranasal delivery of the vector and package, 75 mice were tested with standard behavioral assays measuring mouse anxiety. For example, anxious mice will choose to spend more time in dark areas and tend to bury unfamiliar objects such as marbles in sawdust rather than letting them be. Treated mice spent 35.7 percent more time in light areas than controls and showed a 14.8 percent decrease in the number of marbles buried compared with controls. Mice treated with the CRISPR package showed an 8.47-fold decrease 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.”

The research is still in its early stages and, thus far, has only been tested on mice. However, it does look promising for human trials.

No details were given in the statement as to when these human trials may begin, but the development does indicate that certain traits relating to high anxiety can be modified long-term. This revelation has important implications for the development of new medications to treat both anxiety and depression, particularly for those who are resistant to the current commonly administered medications.

The study was published in PNAS NEXUS.

Study abstract:

The expanding field of precision gene editing using CRISPR/Cas9 has demonstrated its potential as a transformative technology in the treatment of various diseases. 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. In vitro, exposure to primary mouse cortical neurons to AAV9 vectors targeting the HT2RA gene led to a concentration-dependent decrease in spontaneous electrical activity following multielectrode array (MEA) analysis. In vivo, at 5 weeks postintranasal delivery in mice, analysis of brain samples revealed single base pair deletions and nonsense mutations, leading to an 8.46-fold reduction in mRNA expression and a corresponding 68% decrease in the 5HT-2A receptor staining. 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.