Moderna Announces Recent Advances in mRNA Technology Platform to Improve Delivery and Stability
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Moderna Announces Recent Advances in mRNA Technology Platform to Improve Delivery and Stability.
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Moderna Announces Recent Advances in mRNA Technology Platform to Improve Delivery and Stability.
On May 17, Moderna held its fifth Science and Technology Day event. The success of mRNA technology in the development of COVID-19 vaccines has also made the mRNA technology platform a hot spot in the industry.
As a biotech company that has been working in the mRNA space for a decade, Moderna has been working to expand the clinical application of its mRNA technology platform, and in today’s Science and Technology Day report, the company introduced improvements in the delivery and stability of mRNA therapeutics.
Recent Advances in Inhaled mRNA Delivery Technology
Moderna’s executives pointed out in the report that as of the first quarter of 2022, Moderna’s R&D pipeline contains 46 R&D projects, covering a variety of different treatment modalities.
Different treatment modalities require different means of delivering mRNA, including subcutaneous injection, intramuscular injection, intracardiac injection, intratumoral injection, intravenous infusion, and inhalation delivery.
Most mRNA delivery methods require mRNA to be encapsulated in lipid nanoparticles (LNPs), which are composed of multiple lipids, and their formulations need to be optimized for the best delivery.
Previously, Moderna has developed different LNP formulations for intramuscular, intravenous and intratumoral injection. In today’s report, the company highlights the development process of the inhaled LNP formulation.
▲LNP is the main way to deliver mRNA therapy (Image source: Moderna’s official website)
For lung diseases, inhaled mRNA therapy can maximize the concentration of drugs in the lungs compared with other delivery methods, and can be used to treat a variety of diseases, such as cystic fibrosis (CF), tuberculosis, COVID-19 pneumonia, chronic Obstruction of the lungs, etc.
However, the successful development of inhaled mRNA therapy requires addressing multiple challenges, including the ability to deliver mRNA to target cells, express proteins in cells, and maintain LNP function after nebulization.
The Moderna researchers initially found that mRNA delivered using previous formulations of LNPs did not efficiently drive reporter protein expression in lung epithelial cells. So they used a variety of techniques to track LNPs and mRNAs.
They tagged LNPs with fluorescent pigments, tagged proteins expressed by mRNAs, and used new techniques to track the production of new polypeptide chains on ribosomes.
These techniques allow researchers to determine at which step after inhaled mRNA therapy enters the lungs, it is blocked, preventing the lung epithelial cells from expressing the protein.
▲Technology for tracking inhaled mRNA delivery and protein expression (Image source: Moderna’s official website)
Studies using in vitro lung tissue models found that although mRNA-carrying LNPs were taken up by 60% of lung epithelial cells, only 1% of cells expressed the protein encoded by the mRNA.
This means that although mRNA successfully enters the endosome of the cell, only a few mRNA molecules can escape from the endosome and drive protein synthesis in the cytoplasm.
Based on this understanding of the details of the mRNA delivery process, the researchers focused on improving the LNP formulation while maintaining the efficiency of cellular uptake of LNP, optimizing protein expression, and ultimately significantly increasing the expression levels of mRNA delivered by the inhaled LNP formulation in lung epithelial cells .
▲Optimizing LNP absorption and protein expression for LNP formulations for pulmonary delivery (Image source: Moderna’s official website)
In a non-human primate model, aerosol-delivered inhaled mRNA drugs are able to drive widespread protein expression in the airway epithelium.
Image source: Morderna official website
Moderna has partnered with Vertex to develop an inhaled mRNA therapy expressing CFTR for the treatment of cystic fibrosis.
The co-developed therapeutic candidate is expected to submit an IND application in the second half of this year, and then initiate clinical trials.
Recent Advances in Improving mRNA Drug Stability
mRNAs are inherently unstable, so if they are to be developed into therapeutics, improving the stability of mRNAs has very real implications in extending drug storage time and shelf life.
In their study, researchers at Moderna found that ionizable tertiary amines in LNP formulations can chemically react with mRNA to form adducts.
This adduct results in the inability of the mRNA to be translated, thereby reducing the expression of the protein encoded by the mRNA.
Since this ingredient is present in many LNP formulations containing ionizable lipids, this mechanism of reduced mRNA expression may be present in LNP products widely used in the industry.
Image source: Moderna’s official website
The company’s research points to the need to use different means to reduce adduct formation during the production of mRNA-carrying LNPs, which could lead to multiple benefits, including improved product shelf-life and the ability to store products at higher temperatures, And maintain product activity and consistency between manufacturing batches.
For example, Moderna points out that the use of Tris buffer reduces adduct formation, allowing long-term storage of mRNA products at 2-8°C.
In Moderna’s Science and Technology Day report, the company also presented in vivo biodistribution data for the intramuscular mRNA vaccine, as well as the company’s model to guide vaccine dose selection.
Attached PPT
References:
[1] MODERNA ANNOUNCES ADVANCEMENTS IN MRNA PLATFORM SCIENCE FOR APPLICATION ACROSS MULTIPLE DISEASES AT SCIENCE AND TECHNOLOGY DAY. Retrieved May 17, 2022, from https://investors.modernatx.com/news/news-details/2022/Moderna-Announces-Advancements-in-mRNA-Platform-Science-for-Application-Across-Multiple-Diseases-at-Science-and-Technology-Day/default.aspx
[2] Moderna Science & Technology Day 2022. Retrieved May 17, 2022, from https://s29.q4cdn.com/435878511/files/doc_presentations/2022/05/Science-Day-2022-Master-Slides-FINAL-(05.17_7am).pdf
Moderna Announces Recent Advances in mRNA Technology Platform to Improve Delivery and Stability.
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