SEOUL, March 10 (AJP) - A joint research team from the Korea Advanced Institute of Science and Technology (KAIST) and the Catholic University of Korea has developed a new mRNA platform designed to maintain high therapeutic efficacy in elderly and obese populations. The technology improves the production of therapeutic proteins by optimizing specific regulatory sequences within mRNA molecules, addressing a major limitation where current treatments lose effectiveness due to age or metabolic conditions.
While mRNA vaccines gained global recognition during the COVID-19 pandemic, their performance can vary significantly depending on the biological environment of the recipient. In older individuals or those with obesity, high levels of oxidative stress often hinder the process by which cells translate genetic instructions into functional proteins. This reduced efficiency has remained a hurdle for the broad application of next-generation RNA therapeutics.
To overcome this, the researchers focused on the 5' untranslated region (5' UTR) of the mRNA. This segment does not encode the protein itself but acts as a control center that dictates the volume and speed of protein synthesis. By analyzing vast amounts of biological big data, including tissue transcriptomes and individual cell expression patterns, the team identified specific 5' UTR sequences that remain resilient under cellular stress.
The research utilized multiple advanced analytical techniques, such as RNA sequencing and ribosome profiling, to minimize bias across different species and cell types. The team discovered that their newly designed sequences are regulated by specific protein factors, including LARP1 and LARP4. These factors allow the mRNA to continue producing proteins effectively even when standard cellular pathways are compromised by aging or obesity.
Preclinical trials using animal models confirmed that the optimized mRNA platform significantly improved both protein expression and immune responses. Unlike conventional mRNA sequences that showed decreased performance in aging and obesity models, the newly engineered sequences maintained high levels of activity.
"This research establishes a design methodology that allows mRNA to produce proteins more effectively by leveraging large-scale biological datasets," said Professor Lee Young-suk of the KAIST Department of Bio and Brain Engineering. "It provides a foundation for ensuring that mRNA vaccines and treatments remain reliable for patient groups where drug efficacy is typically lower, such as the elderly or those with obesity."
The study, led by Professor Lee Young-suk and Professor Nam Jae-hwan of the Catholic University of Korea, featured Yoon Su-bin and Cho Hyeong-gon as joint first authors. The findings were published online in the international journal Molecular Therapy on January 2.
(Paper information)
Journal: Molecular Therapy (impact factor: 12.0)
Title: Designing 5' UTR sequences improves the capacity of mRNA therapeutics in preclinical models of aging and obesity
DOI: https://doi.org/10.1016/j.ymthe.2025.12.060
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