Researchers developed a new gene editing technique that reduces anxiety in mice.
The technique uses CRISPR technology to edit a specific gene in the brain called HTR2A.
Editing this gene leads to lower levels of anxiety behaviors in tests with mice.
This research demonstrates the potential of using gene editing tools like CRISPR to precisely target genes involved in brain disorders like anxiety.
Key Facts:
- CRISPR was used to edit the HTR2A gene in the brains of mice
- Lower levels of the HTR2A gene were linked to less anxious behaviors in mice
- Gene editing was delivered through the nose, bypassing the blood brain barrier
- Technique reduced anxious behaviors in multiple tests including mazes and light/dark boxes
- Shows promise for treating anxiety, depression, and other brain disorders
Source: PNAS Nexus. 2023 Jun; 2(6): pgad170.
What is CRISPR Gene Editing?
CRISPR (pronounced “crisper”) stands for Clustered Regularly Interspaced Short Palindromic Repeats.
It is a gene editing technology that can precisely cut and modify targeted genes.
CRISPR uses special molecular scissors called Cas9 along with a guiding system to make cuts in specific genes.
Once the cut is made, the cell’s repair machinery kicks in to fix the break.
This often introduces small errors which disrupt the gene’s function.
By disrupting a disease-causing gene, CRISPR may be able to treat genetic conditions.
CRISPR is revolutionizing medical research due to its precision, ease of use, and low cost compared to previous gene editing methods.
Dozens of CRISPR clinical trials are underway for treating sickle cell anemia, cancer, blindness, and other diseases.
However, delivering CRISPR to the brain has been a major challenge due to the blood-brain barrier which blocks entry of most molecules.
Finding safe and effective ways to get CRISPR into the brain could enable a new era of treatments for psychiatric and neurological diseases.
Targeting the Anxiety Gene HTR2A (5HT2A)
The researchers focused on using CRISPR to reduce anxiety by editing a gene called HTR2A.
This gene provides instructions for making a specific serotonin receptor protein called 5-HT2A.
Serotonin is a neurotransmitter involved in regulating mood, anxiety, appetite, and sleep.
The 5-HT2A receptor is found in various parts of the brain including areas implicated in anxiety and depression.
Previous research suggests that lower 5-HT2A receptor levels are linked to reduced anxiety.
Currently available anti-anxiety medications like SSRIs work in part by decreasing 5-HT2A receptor activity.
However, these drugs impact the entire serotonin system leading to side effects and incomplete treatment response in many patients.
The researchers hypothesized that using CRISPR to precisely edit the HTR2A gene could lower 5-HT2A receptor levels specifically.
This gene-targeting approach could reduce anxiety while avoiding broad systemic effects of current drug therapies.
Delivering CRISPR to the Brain through the Nose
Getting the CRISPR editing tools into the brain was accomplished through an intranasal delivery method.
Intranasal administration involves spraying or dripping a solution into the nose so that it can be absorbed and transported into the brain.
The researchers used a specially engineered adeno-associated virus called AAV9 to package and carry the CRISPR components.
When delivered intranasally, the AAV9 particles were able to travel along olfactory nerve pathways from the nose into the brain.
This allowed the CRISPR gene editing cargo to bypass the blood-brain barrier for delivery to neurons throughout the central nervous system.
Testing CRISPR’s Effects on Neurons and Anxiety
To test the CRISPR-HTR2A approach, the researchers conducted experiments with mouse neurons grown in dishes as well as studies in live mice.
They first exposed mouse brain cells to the CRISPR therapy and measured the effects on neuron activity.
Results showed up to an 80% drop in electrical signaling between the treated neurons.
This demonstrated that CRISPR editing successfully disrupted the HTR2A gene, leading to less active 5-HT2A receptors.
In mice, intranasal treatment led to CRISPR edits being detected in brain regions involved in anxiety circuits.
Edits were found in cortex, cerebellum, and other deep structures.
Staining of brain sections showed a 68% reduction in 5-HT2A receptor levels compared to untreated mice.
Most importantly, the gene edited mice displayed less anxiety behaviors.
In maze tests assessing anxious tendencies, CRISPR treated mice spent more time in open illuminated spaces.
They also buried fewer marbles, another anxious behavior in mice.
The reductions in anxiety were comparable to the anti-anxiety effects of medications like Valium.
Future Outlook for Brain Gene Editing
This research provides an important proof of concept for using CRISPR to edit genes directly in the brain as a therapeutic strategy.
While safety and ethical concerns remain, the approach shows promise for precisely treating neurological and psychiatric conditions at their genetic source.
If the intranasal delivery and gene targeting can be optimized, CRISPR therapies could eventually be developed for anxiety, depression, PTSD, obsessive compulsive disorder, and other disorders involving dysregulated brain circuits.
The ability to pinpoint causal genes gives gene editing advantages over current treatments that indirectly influence entire neurotransmitter systems.
However, significant work remains to scale up this approach for real world human applications.
Challenges include improving the efficiency of editing within neurons, testing anxiety gene modifications in human cells, and demonstrating that behavioral improvements persist long-term.
There is also a need to evaluate the risks of off-target effects which could impact other genes.
With continued research advances, gene editing may usher in a new generation of personalized, highly specific medical therapies for psychiatric diseases.
But ensuring such treatments are safe and ethical remains imperative as the field progresses.
For now, CRISPR’s application in improving mental health remains an exciting prospect for the future.
References
- Study: Genetic modulation of the HTR2A gene reduces anxiety-related behavior in mice
- Authors: Troy T. Rohn et al. (2023)
