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Synthetic mRNA Therapies in Rare Diseases

Since the COVID-19 pandemic, the world of synthetic mRNA therapies has been exploding with newfound interest and research. Research fields utilizing mRNA include vaccinations, cancer therapies, immunotherapies, and protein replacement therapies. Regarding rare diseases and genetic disorders, protein replacement therapy is very useful as it provides an avenue for missing proteins to be encoded by synthetic mRNA and produced by utilizing the patient’s own cell machinery.


DNA is well known for its double helix structure that provides high levels of stability, meanwhile the single helix structure of RNA provides a high level of variability and versatility. While there are several forms of RNA with the ability to be manipulated as therapeutics, the most common is small interfering RNA (siRNA), which targets a single mRNA target, making it a great therapeutic candidate. Synthetic mRNA therapies utilize the cell’s ribosomal machinery by providing an engineered mRNA molecule that is encoded to produce a desired protein into a patient’s cells. Upon uptake into the cell the mRNA is then translated, and the encoded target protein is produced. Synthetic mRNA is meant to function transiently and is degraded by nucleases, allowing the cell to maintain a flexible response and quickly adapt to the cellular environment. Nevertheless, the high mRNA decay was optimized.

Synthetic mRNA has been researched since the 1990’s, over the years many strides in optimization were made. In 2005 it was found by Drew Weissman and Katalin Kariko that cell survival and protein translation could be improved by altering the mRNA nucleotides to avoid pattern recognition receptors (PRR) and prevent an excessive immune response that would end protein translation. When it comes to protein expression and translation efficiency, nucleotide modification and codon optimization are important factors. Codon optimization is a technique that involves modifying the mRNA sequence to match the codon usage bias of the target cells, which then improves translation efficiency and protein production. By customizing mRNA sequences to match the codon usage of the target cells, researchers can create more effective and precise therapies for patients. Another landmark in mRNA therapy optimization is the delivery platform. mRNA’s sensitivity to hydrolytic and nuclease degradation makes synthetic mRNA therapy flexible and agile, but also provides a challenge when trying to deliver treatment. A promising solution is the use of lipid nanoparticles to encapsulate and transport the mRNA through the body and through the cell membrane by endocytosis.

Overview of mRNA encapsulated in LNPs

Overview of mRNA encapsulated in LNPs
‘Figure 1. Overview of mRNA encapsulated in LNPs [lipid nanoparticles]. mRNA structure includes the classical elements required for ribosome translation: cap, 5’ UTRs, ORF, 3’ UTRs, and poly(A) tail. Encapsulated in LNPs, mRNA is delivered to targeted cells via endosome escape and translated into protein following endosomal escape. Proteins can be translocated to the designated organelles or secreted based on their natural signal peptides. LNPs, lipid nanoparticles; mRNA, messenger RNA; ORF, open reading frame; UTRs, untranslated regions.’ Martini, 2019

Current state of research

A great example of synthetic mRNA therapy development for the treatment of rare disease today is seen in the research for alternative treatment options for patients with Methylmalonic Acidemia (MMA). MMA is a rare autosomal recessive disorder caused by methylmalonyl-coenzyme A (CoA) mutase (MUT) deficiency and is characterized by elevations of methylmalonic acid in tissues and body fluids. Currently the only treatment options available for patients are diet, supplements, antibiotics, and liver transplantation. In recent in vivo studies by Dr. Charles Venditti and colleagues, use of systemic mRNA therapy to restore the defective methylmalonyl-CoA enzyme was found to reduce methylmalonic acid levels in plasma by 60-90% and maintain lowered levels for up to two weeks in MMA mut mice. This reduction has similar efficacy to liver transplantations and offers a significantly less invasive treatment option that is reversable if needed. A common concern with mRNA therapies is the production of antibodies against the introduced mRNA after repeated doses, however, the MUT mRNA study showed no elevations in these antibodies after 5 repeated treatments. Clinical trials for the therapy were funded, approved, and organized, but were terminated prior to dosing due to a business decision independent from the safety and efficacy of the trial. This presents mRNA therapy as a viable and effective potential treatment method for targeting liver damage caused by this ultra-rare disease.


In conclusion, the COVID-19 pandemic has ignited a surge of interest and research in synthetic mRNA therapies. With advances in mRNA optimization techniques, such as codon optimization and delivery platforms like lipid nanoparticles, researchers can develop more precise and effective therapies for patients. The promising results seen in the use of systemic mRNA therapy to treat Methylmalonic Acidemia demonstrate the potential of mRNA therapy to offer minimally invasive and reversible treatment options for rare diseases. Although concerns remain about the production of antibodies after repeated doses, the MUT mRNA study showed no elevations in these antibodies after multiple treatments, suggesting that mRNA therapy may be a viable and effective treatment option. The ongoing development and refinement of mRNA therapies holds great promise for revolutionizing the field of medicine and improving the lives of patients in need.


Elastrin Therapeutics is developing a synthetic mRNA therapy delivered via our DESTiNED platform that will encode Tropoelastin (TE) for the de novo synthesis of elastin within cells. This treatmentcould be revolutionary for patients with Williams-Beuren Syndrome (WBS), which is characterized by a deletion of the elastin gene (ELN) and results in only the half amount of elastin protein in WBS patients resulting in moreover cardiovascular anomalies. Elastrin’s Tropoelastin mRNA therapy could allow WBS patients to produce and replace missing elastin caused by the ELN deletion. For more information regarding Williams-Beuren Syndrome please reference our previous article ‘Diving deeper into orphan diseases - Williams-Beuren Syndrome (WBS)’.

  • Cooke JP, Youker KA. Future Impact of mRNA Therapy on Cardiovascular Diseases. Methodist DeBakey Cardiovasc J. 2022;18(5):64-73. doi: 10.14797/ mdcvj.1169

  • Martini PGV, Guey LT. A New Era for Rare Genetic Diseases: Messenger RNA Therapy. Hum Gene Ther. 2019 Oct;30(10):1180-1189. doi: 10.1089/hum.2019.090. Epub 2019 Jul 1. PMID: 31179759.

  • Valsecchi, MC. Rare Diseases The Next Target For mRNA Terapies. Nature Italy. 2021 May, 9.

  • Fu, H., Liang, Y., Zhong, X. et al. Codon optimization with deep learning to enhance protein expression. Sci Rep 10, 17617 (2020).


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