Study Offers Safer Path for mRNA Therapeutics Development

The remarkable success of mRNA vaccines in combatting COVID-19 has ignited a surge of interest in leveraging this technology to develop vaccines and treatments for a myriad of diseases, including rare conditions and cancer. However, before these promising mRNA therapeutics can be deployed, rigorous assessments of their safety and toxicity must be conducted at the preclinical stage. A recent paper published in Nature Reviews Drug Discovery, co-authored by Northeastern professor Mansoor Amiji, offers insights into various strategies to evaluate toxicity without relying on problematic animal testing. 

Amiji, a distinguished professor of pharmaceutical sciences and chemical engineering, highlights the pivotal moment the mRNA field is experiencing, exploring its potential beyond COVID-19 vaccines. He emphasizes the need to ensure the safety of mRNA therapeutics and lipid nanoparticles used for delivery, outlining strategies to identify and mitigate potential red flags during development. 

One of the key advantages of mRNA technology lies in its ability to instruct cells to produce specific proteins involved in treating diseases and preventing infections. Unlike traditional vaccines that rely on weakened or dead viruses, mRNA vaccines prompt the body to generate a fragment of the virus, eliciting an immune response. Moreover, the rapid manufacturing process of mRNA vaccines contrasts sharply with the time-consuming production of conventional vaccines. 

Amiji underscores the importance of early screening for toxicities, advocating for the use of innovative technologies such as lab-grown human cells and organs. Detecting toxicities at an early stage not only enhances patient safety but also minimizes costs for companies developing new therapeutics. The imperative to “fail early” in drug development reflects the pharmaceutical industry’s commitment to avoiding substantial financial losses associated with late-stage clinical trial failures. 

The paper highlights RNA toxicity as a potential concern, wherein mRNA’s role in protein synthesis may lead to the loss of protein function. Additionally, the lipid nanoparticles used to deliver mRNA can induce toxicities, necessitating thorough safety evaluations. The risk of toxicity varies depending on factors such as patient health and dosing frequency, with immunocompromised individuals or those receiving frequent doses being particularly vulnerable. 

Moreover, the reliance on animal testing in preclinical safety assessments presents its own set of challenges. While mouse models and non-human primates are commonly used, their predictive value for human responses is limited. This was evident in COVID-19 vaccine trials, where vaccines deemed safe in initial phases showed unexpected toxicities when administered to larger populations. Amiji stresses the need for caution in extrapolating safety data from animal models to humans, advocating for more robust preclinical testing methodologies. 

The potential of mRNA therapeutics to revolutionize healthcare is immense, but ensuring their safety remains paramount. Amiji underscores the critical questions surrounding the long-term safety of mRNA treatments, especially regarding repeat dosing and consistent protein expression. Balancing efficacy with safety is essential in maximizing the benefits of mRNA technology while minimizing risks to patients. 


In conclusion, the paper by Professor Mansoor Amiji and colleagues sheds light on the complexities of evaluating the safety of mRNA therapeutics. By proposing innovative strategies to assess toxicity at the preclinical stage, the research paves the way for safer and more effective mRNA-based treatments. As the field continues to evolve, rigorous safety evaluations will be crucial in realizing the full potential of mRNA technology in combating a wide range of diseases. 

Journal Reference  

Dimitrios Bitounis et al, Strategies to reduce the risks of mRNA drug and vaccine toxicity, Nature Reviews Drug Discovery (2024). DOI: 10.1038/s41573-023-00859-3.  

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