A recent study published in Genomic Psychiatry has unveiled a promising new therapy that may help improve memory and reduce anxiety. The study, conducted by scientists at Cognigenics, explores the potential of an innovative intranasal treatment known as COG-201. This therapy uses RNA-based technology to decrease the activity of a specific serotonin receptor in the brain, leading to significant improvements in memory and reductions in anxiety-like behaviors in rodent models.
The motivation behind the study lies in the significant public health burden posed by neurological conditions like mild cognitive impairment (MCI) and anxiety disorders. MCI is often viewed as a transitional state between normal aging and dementia, affecting millions worldwide. Anxiety disorders are also highly prevalent, frequently co-occurring with cognitive decline. Currently, no single treatment addresses both cognitive impairment and anxiety, and the available therapeutic options are limited.
Given these challenges, the researchers set out to explore an innovative treatment approach using RNA interference (RNAi), a genetic technique that can selectively reduce the activity of specific genes. The target of their therapy, the serotonin 5-HT2A receptor, plays an essential role in regulating mood, anxiety, and cognitive functions. By focusing on this receptor, the researchers aimed to develop a therapy that could improve both memory and anxiety symptoms simultaneously, offering hope for more comprehensive treatment options.
“My struggles with anxiety and my relentless pursuit of novel treatment options have significantly fueled my dedication to this field of work. Gene therapy, such as COG-201, described in our most recent publication, offers that hope; I argue that these tailor-made medications are the future of therapeutics,” said Troy T. Rohn, the director of preclinical studies for Cognigenics, a professor of biology at Boise State University, and the lead author of the study.
The study used COG-201, an intranasal therapy based on short hairpin RNA (shRNA). This RNA molecule is designed to interfere with the expression of the serotonin 5-HT2A receptor gene, reducing its activity in the brain. The therapy was administered through a nasal spray, making it non-invasive and potentially easy to use in future clinical settings.
To evaluate the therapy’s effects, the researchers conducted experiments on animal models, specifically mice and rats. They first developed a shRNA designed to reduce the production of the serotonin 5-HT2A receptor by targeting its gene, HTR2A. The treatment was delivered using an adeno-associated virus (AAV9) vector, which served as a carrier to transport the shRNA into the neurons.
The researchers assessed the animals’ memory and anxiety levels using established behavioral tests. For memory, they employed the novel object recognition test, which measures how much time animals spend exploring new objects versus familiar ones. Animals with better memory are expected to spend more time investigating new objects. To evaluate anxiety, they observed the animals’ behaviors in environments that typically elicit anxiety-like responses, such as open fields or elevated platforms.
The study also included an in-depth analysis of how the therapy affected the brain on a molecular level. The researchers examined brain tissue from treated animals to confirm that the shRNA successfully reduced the expression of the serotonin 5-HT2A receptor. They used a combination of real-time polymerase chain reaction (PCR) and Western blot techniques to measure the receptor’s mRNA and protein levels in the brain. Additionally, they monitored the electrical activity of neurons in cultured brain cells to determine how reducing the receptor’s activity affected overall brain function.
The results of the study were promising. Animals treated with COG-201 displayed significant improvements in memory and reductions in anxiety-like behaviors. In the novel object recognition test, treated rats spent considerably more time exploring new objects compared to untreated animals, indicating better memory retention. The researchers calculated a discrimination index, a measure of memory performance, and found that the treated group scored 22.5% higher than the control group, which exhibited a negative score.
“The profound effects we found on the improvement of memory were very much unexpected,” Rohn told PsyPost. “This was based on the literature that hinted at a possible role of the 5-HT2A receptor in memory, but it certainly was not a role written in stone.”
On the anxiety front, the treated animals showed reduced anxiety-like behaviors in anxiety-inducing environments. This suggested that COG-201 may have a dual benefit: improving memory while also alleviating anxiety.
The molecular data supported these behavioral findings. The researchers confirmed that the intranasal delivery of COG-201 effectively reduced the expression of the serotonin 5-HT2A receptor in the brains of both mice and rats. There was a 38% reduction in receptor mRNA levels and a corresponding 34% decrease in receptor protein levels in treated neurons. This knockdown of receptor expression was directly linked to changes in neuronal activity. Neurons in treated animals showed a decrease in electrical activity, which aligns with the theory that reducing serotonin 5-HT2A receptor activity could dampen the excitatory signals that contribute to anxiety and memory deficits.
Furthermore, the study revealed that while individual neurons showed reduced activity, there was an increase in synchronized network activity among groups of neurons. This suggests that COG-201 may enhance the brain’s ability to coordinate information processing, which could explain the improvements in memory.
“The evolution of gene therapy from a science fiction plot to a tangible real-world solution with the potential to revolutionize the way anxiety and various neuropsychiatric conditions are treated is genuinely remarkable,” Rohn said. “I am excited about the impact our work at Cognigenics may have in motivating scientists, patients, and healthcare professionals to explore possibilities for advancements in medicine and patient care as we enter a promising era of personalized treatment options tailored to individual needs. I believe gene therapy is set to become the landmark medical breakthrough of the 21st century, offering solutions to various diseases and ushering in what I believe will be the Golden Age of Medicine.”
While the findings from this study are encouraging, there are some important limitations to consider. First, the experiments were conducted in animal models, and results from such studies do not always translate directly to humans. The researchers acknowledged that while rodents are useful for initial testing, their brain structure and function differ from humans in significant ways.
“The major caveat is that rodent models may not directly translate to human central nervous system (CNS) diseases,” Rohn noted. “Also, considering the immense olfactory region in rodents, translating the ability of COG-201 to gain entry into the brain via intranasal delivery is not certain.”
Looking ahead, the researchers plan to continue studying the mechanisms behind COG-201 and its potential to treat other conditions beyond mild cognitive impairment and anxiety. They are particularly interested in exploring how the therapy could be adapted to target other receptors and conditions, paving the way for a new class of RNA-based treatments for neurological disorders.
A key goal is “gaining approval to start human clinical trials of COG-201,” Rohn said. “We are also interested in using our platform to potentially target other receptor systems to target currently untreatable diseases.”
“We have struggled in the past nine months to obtain the necessary capital to take us into clinical trials,” he added. “I now realize how naive my academic mind was in understanding the world of venture capitalists.”
“My thinking was akin to the quote from Field of Dreams: ‘If you build it, they will come.’ In the past five years, we have accumulated robust proof-of-concept data for our gene therapy strategy, so naturally, in my mind, the money would follow. Through these experiences, I have realized that creating a foundation of science does not necessarily lead to financial backing, especially in the volatile realm of venture capital, where success often depends on factors beyond having reliable preclinical data.”
The study, “Treatment with shRNA to knockdown the 5-HT2A receptor improves memory in vivo and decreases excitability in primary cortical neurons,” was authored by Troy T. Rohn, Dean Radin, Tracy Brandmeyer, Peter G. Seidler, Barry J. Linder, Tom Lytle, David Pyrce, John L. Mee, and Fabio Macciardi.
