By Yochi Slonim, CEO and co-founder of Anima Biotech
mRNA technology has gained widespread recognition due to its role in the development of vaccines, such as those used against COVID-19; however, the scope of mRNA extends far beyond vaccines, offering a range of applications for addressing different conditions.
Vaccines represent a notable application of mRNA technology. Synthetic versions of mRNA are used to train the immune system against specific viruses without exposing the body to live pathogens. This breakthrough approach has provided a foundation for combating infectious diseases.
Another significant area of mRNA technology is RNA interference (RNAi). RNAi utilizes short RNA molecules to block or “knock down” specific mRNA molecules, thereby suppressing the production of their corresponding proteins. RNAi has limitations, including challenges related to delivery through injections and its “one-way street” nature.
While RNAi drugs have the advantage of relatively low risk of systemic side effects, as they tend to have minimal impact on tissues outside of the injection site, they are unable to treat diseases where proteins are under-expressed. Additionally, the rapid degradation of RNAi drug molecules presents a hurdle in achieving effective delivery.
With mRNA vaccines and RNAi drugs are already available, the biology of mRNA has emerged as a strongly validated “drug mine.”
Small molecule mRNA drugs
The development of small molecule mRNA drugs has garnered significant attention, with this approach holding enormous promise due to its broad applicability, low costs and potential for self-administration.
To date, approaches to the discovery of small molecule mRNA drugs have taken two different directions.
Initial attempts involved targeting the mRNA molecule directly, which is akin to the mechanism of RNAi. The drug binds to the mRNA transcript and interferes with its biology. However, this approach faces challenges due to the complex chemistry of RNA, making it difficult for small molecules to bind effectively.
Specificity is another major issue, as small molecules have the potential to be delivered to every cell in the body. If the target mRNA is expressed in multiple tissues, small molecule mRNA drugs may bind in unexpected ways, potentially leading to off-target effects. Furthermore, this approach retains the limitation of being a “one-way street”, as there is no way to encourage cells to produce more of an under-produced protein.
At the cutting edge of mRNA therapeutics, a new approach involves small molecules that interact with the mechanisms of action used by cells to regulate mRNA biology. These molecules have the ability to both decrease and increase protein production, offering a “two-way street” for potential treatment. This approach provides a higher level of selectivity and the potential to treat a much broader range of diseases.
In this fast-developing and highly promising space, most companies are “betting” on specific mechanisms of action (MOA), such as RNA binding proteins (RBPs), splicing factors, mRNA modifying enzymes and others. Yet our understanding of mRNA biology is still in its early stages, and betting on a specific target may be misguided. In such situations, phenotypic screening using mRNA imaging and visualization technology emerges as a promising approach. This technique allows researchers to visualize the effects of millions of tested molecules on mRNA biology and advance the compounds producing the desired effects.
The explosion of artificial intelligence (AI) in drug discovery further enhances our ability to unlock the potential of mRNA biology. Combined, phenotypic screening and the advanced capabilities of high content mRNA imaging, create an extraordinary “visual drug mine” of billions of mRNA images. These images capture the impact of millions of tested molecules on the mRNA of interest, offering invaluable insights.
AI systems can be trained on billions of examples to recognize active molecules and gain insights into their mechanisms of action. This mechanism of action elucidation with AI (MOAi) enables us to avoid relying solely on a single mechanism. Instead, we identify active molecules first and rapidly elucidate their MOA.
mRNA technology has extended far beyond its initial applications
In summary, the realm of mRNA technology has extended far beyond its initial applications in vaccines, paving the way for the emergence of small molecule mRNA drugs with vast therapeutic potential. Despite the challenges that lie ahead, ongoing research endeavors, along with phenotypic screening coupled with state-of-the-art mRNA imaging technologies and the integration of AI, hold promise for tackling diseases that were once considered undruggable.
Strategic collaborations and partnerships will play an indispensable role in bolstering innovative companies as they navigate the intricate landscape and seize the opportunities that await. As we delve deeper into the remarkable capabilities of mRNA technology, we find ourselves standing at the precipice of a transformative era in medicine, poised to revolutionize healthcare and deliver groundbreaking therapies to patients in need.
Partnering 2030: The Biotech Perspective 2023