mRNA-Based Drug Pharmacology Optimization Platform

Given the advantages over DNA and recent progress that has been made in the field of mRNA, researchers have renewed interest in mRNA-based drugs. However, mRNA-based drugs suffer from several inherent challenges, including inefficient protein translation, intrinsic instability, and immune response activation following transfection. Creative Biogene is a leading provider in the field of mRNA R&D service. We have developed a pharmacology optimization platform to overcome the issues of this drug class. We are committed to systematically improving the intracellular stability and potency of mRNAs, aiming to provide the basis for a broad spectrum of potential applications.

Basic mRNA based-drug pharmacology

Large quantities of mRNA can be yielded by in vitro transcription from DNA templates using phage RNA polymerase. In vitro-transcribed (IVT) mRNA is designed to structurally resemble naturally occurring mature and processed mRNA in the cytoplasm, translating the message to the desired corresponding protein, the pharmacologically active product. In other words, the synthetic mRNA for therapy is designed following the blueprint of eukaryotic mRNA, including 5' cap, 5' and 3' untranslated region (UTR), open reading frame (ORF), and 3' poly adenosine (poly(A)) tail. To achieve the bioavailability of mRNA-based drugs, the desired corresponding protein should be delivered to the right cellular compartments, which encounter the two major challenges, including regulation of the stability of mRNAs and the development of available delivery systems. The half-life of the mRNA as well as the resulting mature protein determine the pharmacokinetics of IVT mRNA.

Fig1. A typical mRNA construct. (Versteeg, L., et al. 2019)

Strategies for enhancing mRNA stability

To deal with the inherent lack of mRNA stability and further promote protein translation, we have developed two main strategies, including molecular stabilization and formulation strategies (please refer to delivery nanosystems platform). We focus on all the structural elements of synthetic mRNA when implementing the molecular stabilization strategy, providing a series of mRNA optimization services, listed as below,

• Cap analog synthesis
• Elongation of the poly(A) tail
• Modulation of untranslated regions (5' and 3' UTR)
• Engineering of the sequence patterns in the ORF

Strategies for modulation of immunogenicity

After being transported to the host cell, the mRNA is detected and recognized by the cellular activated various pattern recognition receptors (PRRs), such as toll-like receptors (TLR) and RNA-dependent protein kinase (PKR). The immunostimulatory property of exogenous mRNA is double-sided. According to different therapeutic applications, we provide the following strategies to shape the immunostimulatory profile of IVT mRNA.

• A series of purification protocols, such as HPLC, FPLC, and magnetic beads technology
• Introduction of modified nucleosides
• Addition of adjuvants

Creative Biogene is a leading provider in the field of mRNA R&D service. We continuously challenge ourselves and strive to offer our customers the finest service. To initiate or advance your project, please feel free to contact us or directly send us an inquiry.