Proteins are the “workhorses” within cells responsible for metabolic processes, transport processes and structural elements. They are coded by genes on DNA and this code is transcribed into a message (messenger RNA) within the cell nucleus. This messenger RNA then leaves the nucleus and is translated into the protein on ribosomes (Figure 1). Many genetic diseases are the result of a key protein not being correctly coded on the DNA resulting in the protein not being made or being defective. Examples include haemophilia which results from a lack of certain clotting factors in the blood and cystic fibrosis where patients do not have a functional transmembrane conductance regulator in lung cells.
Therapeutic messenger RNAs (mRNA) are a new class of nucleic acid drugs directed to treatment of diseases resulting from an inability to produce a key protein. These genetic disorders can in principle be corrected by introduction of mRNA which codes for the missing or defective protein (Figure 2). Expression of a therapeutic mRNA to provide a functional copy of the missing or defective protein has the potential to correct the genetic disorder. Another application of mRNA therapeutics is in the synthesis of protein antigens for next generation vaccines. Protein antigens synthesized from mRNA inside mammalian cells (in situ synthesis) often result in better activation of the host immune system, as this resembles a normal viral infection, thereby increasing vaccine potency. In addition, mRNA can be used to express a therapeutic or prophylatic antibody thus reducing the time taken to develop natural immunity through a typical antigen-mediated vaccination process.
Therapeutic mRNAs however are very large polar molecules which are not able to enter cells by themselves. They therefore require a delivery vehicle to access the cell cytoplasm where they can then be translated into the corresponding therapeutic protein. Acuitas is developing LNP systems effective for in vivo delivery of therapeutic mRNAs. We recently published results from a collaborative study with CureVac examining the ability of our LNP carriers to deliver an mRNA encoding for the protein erythropoietin (Mol Ther doi:10.1038/mt.2015.103). This study showed very high levels of erythropoietin expression in two large animal species after administration of mRNA-LNP (Figure 3). These high levels of erythropoietin stimulated production of reticulocytes and a subsequent increase in total red blood cells (haematocrit). This study confirmed that mRNA-LNP can provide clinically relevant levels of protein expression in vivo giving rise to a pharmacology response.