In vitro transcribed (IVT) messenger RNA (mRNA) has recently come into focus as a potential new drug class to deliver genetic information. Such synthetic mRNA can be engineered to transiently express proteins by structurally resembling natural mRNA. Armed with advanced mRNA technology, Creative Biolabs is devoted to offering mRNA pharmacology optimization services as either individual service or part of a complete project for global customers.
The concept behind using IVT mRNA as a drug is the transfer of a defined genetic message into the cells for the ultimate purpose of preventing or altering a particular disease state. One method is to transfer mRNA into the patient's cells ex vivo. These transfected cells are then adoptively administered back to the patient. The other is the direct delivery of IVT mRNA using various routes. Fig.1 shows the structural elements of IVT mRNA. Each one can be optimized and modified to modulate the stability, translation capacity, and immune-stimulatory profile of mRNA.Fig.1 Structural features of IVT mRNA. (Verbeke, 2019)
IVT mRNA can be created by incorporating naturally occurring modified nucleosides such as 2-thiouridine, pseudouridine, 5-methylcytidine, 5-methyluridine, or N6-methyladenosine into the IVT mRNA. This has been shown to suppress both the intrinsic adjuvant activity of IVT mRNA as well as its inhibitory effects on translation.
mRNA is potentially beneficial for vaccination because it can provide adjuvant activity to drive dendritic cell (DC) maturation and thus elicits a strong sputum and B cell immune response. Our optimization services include the following aspects:
There are two challenges associated with the delivery of IVT mRNA: one is to achieve a sufficiently high net level of the encoded protein and the other is to reach a high number of cells. In vivo delivery of mRNA into a high fraction of defined target cell populations is challenging and depends on the accessibility of target cells. Creative Biolabs found that multiple structural motifs of the amino lipid are important for efficient in vivo performance of mRNA-containing lipid-based nanoparticle (LNP), including surface charge, structure, and position of the ester in the lipid tails and structure of the head group. We have identified lipids that balance chemical stability, improved efficiency of delivery due to improved endosomal escape, rapid in vivo metabolism, and a clean toxicity profile.
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