# Toward synthetic chemically defined mRNA for human therapeutics

> **NIH NIH R21** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $230,891

## Abstract

PROJECT SUMMARY
 Messenger RNA, or mRNA, and its translation into protein lies at the heart of the central dogma of
molecular biology. Converting this basic cellular mechanism into a therapeutic opportunity was the basis
of the first two successful COVID-19 vaccines. This technology has the potential to be further advanced
into much broader therapeutic modalities, such as a gene replacement medicine for genetic diseases.
Currently, mRNA molecules for human therapeutics are generated from biological enzymatic reactions.
While this process can create large amounts of material, it suffers from several drawbacks. These include
multiple steps in manufacturing, purity, and patient safety. However, the greatest shortcoming is the rapid
turnover of mRNA in the body, which severely limits its duration of effect and tunability for a genetic
medicine. Unless addressed, this shortcoming will handicap mRNA therapeutics from ever becoming
more than a vaccine technology.
 Chemical modification was the missing ingredient and final piece necessary for the realization of other
recently FDA-approved nucleic acid drugs, including antisense oligonucleotides and small interfering
RNAs. Chemical modifications enabled nuclease protection, significantly extended drug half-lives, and
predictable pharmacological tuning. Likewise, realizing the full potential of mRNA as a human therapeutic
will ultimately come down to chemistry.
 RNA can be chemically synthesized in small fragments. However, no technology exists to easily
create long chemically defined translation-competent mRNA molecules. In addition, most of the chemical
modifications extensively characterized for their beneficial properties for other nucleic acid therapeutics
have not been explored in mRNA research, and certainly not in a therapeutic context. This project
proposes to tackle these challenges by generating full-length mRNAs from chemically synthesized
fragments, investigating the impact of diverse chemical modifications on mRNA translation, and applying
new synthetic chemical methods to make longer mRNAs suitable for human therapeutics.
 The aims of this proposal are to 1) evaluate the impact of specific nucleotide modifications on model
mRNA translation in cells and in vitro, 2) assess the compatibility of triazole linkages with mRNA
translation and on-resin “click” chemistry for solid-phase chemical synthesis of longer mRNA, and 3)
demonstrate long mRNA chemical synthesis and its potential for therapeutic development in cells and in
vivo. The results of this focused project should pioneer a paradigm-shifting approach to mRNA therapeutic
development and open new possibilities for conferring better control over the drug properties of mRNA.

## Key facts

- **NIH application ID:** 10927440
- **Project number:** 5R21GM150088-02
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Keith Thomas Gagnon
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $230,891
- **Award type:** 5
- **Project period:** 2023-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10927440

## Citation

> US National Institutes of Health, RePORTER application 10927440, Toward synthetic chemically defined mRNA for human therapeutics (5R21GM150088-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10927440. Licensed CC0.

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