mRNA Technology: Transforming Medicine

Messenger ribonucleic acid (mRNA) serves as a carrier of genetic instructions from DNA to the cell machinery for the production of proteins. mRNA technology plays a significant role in the development of therapeutic interventions, exemplified by the incredible success of COVID-19 vaccines (namely COMIRNATY and Spikevax). It holds promise in treating various autoimmune disorders, degenerative disorders, genetic disorders, metabolic disorders, infectious diseases and oncological disorders. Further, mRNA therapeutics offer advantages (over traditional small molecules) such as simpler design, short development cycle, enhanced specificity and long-lasting effect.

Structure of mRNA Technology

mRNA is a single-stranded, long molecule that is complementary to a gene’s DNA. Its key components include:

  • Nucleotides: These are the building blocks of RNA; each nucleotide comprises of a sugar molecule, a phosphate group and nitrogenous bases, namely adenine, guanine, cytosine and uracil.
  • Coding Region: It comprises of codons (set of three nucleotides), which are decoded and translated by ribosome into proteins.
  • Untranslated Regions (UTRs): These are fragments of mRNA that are present before the start codon and after the stop codon.
  • 5’ Cap: The 5’ end of the mRNA is modified with a ‘cap’ structure (comprising of methyl guanosine triphosphate); this cap safeguards the RNA from degradation and supports in initiating the translation process.
  • Poly(A) Tail: The 3’ end of the mRNA has a tail of adenine nucleotides; this string promotes stability and export of mRNA from the nucleus to the cytoplasm.

It is worth mentioning that when the coding region of mRNA codes for a single protein, then it is called as monocistronic (mostly in eukaryotic mRNA) and when the coding region of mRNA codes for more than one protein, then it is called as polycistronic (in case of prokaryotes).

Evolution of mRNA Technology

mRNA Technology Evolution

mRNA Synthesis Process

The mRNA production process is a series of different steps that produce high quality mRNA for application in therapies and mRNA vaccines.

mRNA Technology Synthesis Process

Some additional steps involved in in vitro mRNA synthesis have been described below:

  • mRNA Purification: The process of purification is carried out to remove impurities or by-products from the synthesized mRNA; the different techniques used to purify mRNA include affinity chromatography or filtration techniques.
  • mRNA Characterization: Due to different reasons (such as alteration in temperature or exposure to light occurred during the mRNA manufacturing process), there are chances of mRNA degradation. In order to avoid any alterations in the quality of the product, mRNA characterization is done using RNase mapping, mass-spectrometry and RNA-sequence mapping.
  • Formulation and Stability Optimization: To prevent mRNA from degradation, frozen storage is required along with safety measures taken during the mRNA manufacturing process. Further, lipid nanoparticles are useful in stabilizing the formulations of mRNA.

Applications of Chemical / in vitro Synthesized mRNA

In recent years, the applications of synthetic mRNA production have been elevated due to the progress in the field of mRNA therapeutics post the COVID-19 pandemic. The therapeutics applications related to synthetic (modified) mRNA are being explored. Further, the major areas of therapeutic applications, include mRNA-based gene editing, genetic reprogramming along with protein replacement, infectious diseases vaccines and cancer immunotherapy.

The various applications of chemical / in vitro synthesized mRNA have been briefly described below:

  • Vaccines for Infectious Diseases: mRNA vaccines are becoming a promising tool in case of infectious diseases; notably, various preclinical studies have been executed for the same in the recent past. As compared to conventional vaccines, the mRNA vaccines have high safety profile for different diseases, such as dengue virus, influenza and herpes simplex virus type 2. It is worth mentioning that Moderna, and Pfizer-BioNTech developed COVID-19 vaccines using mRNA-LNP technology.
  • Cancer Immunotherapies: For the treatment of cancer, the delivery technology of modified synthetic mRNA is used preclinically as well as clinically. Further, mRNA vaccines have been formulated as cancer immunotherapies, for the treatment of glioblastoma, colon cancer and leukemia.
  • Antibody Therapies: Administration of mRNA transcripts encoding antibodies allows enhanced and prolonged patient expression of the therapeutic agent.
  • Gene Therapies: In the case of gene related disorders, the mRNA based tools have become more specific to the site which has to be edited in the genome, resulting in curing of the disease.
  • Protein Replacement Therapies: mRNA therapy is useful in replacing intracellular as well as transmembrane proteins, thereby treated several disorders.
  • Regenerative Medicines: mRNA technology is useful in regenerating human cells or tissues, resulting in restoration of normal functioning of the body. Further, the development of mRNA-based therapeutics (BNT162b2) has shown remarkable potency in regenerative medicine.
  • Cell Therapies: Cell therapy uses the specific trained cells for a particular disease to be treated. Further, it can be done in vivo or ex vivo with the use of mRNA technology.

Outsourcing of mRNA mRNA Technology Manufacturing Operations

The mRNA synthesis and manufacturing is a complex process, requiring special expertise. Other mRNA manufacturing challenges include requirement of skilled labor and presence of stringent mRNA manufacturing process protocols. Moreover, stability of drug substances requires specific facilities and cold chain transportation. They also require suitable drug delivery systems to administer the drug substance efficiently. The growing demand for mRNA and lack of mRNA manufacturing capabilities have promoted the developers to outsource operations related to mRNA synthesis. The advantages of outsourced manufacturing operations include:

  • Companies can focus on their core competencies
  • Gaining access to advanced capabilities and specialized knowledge of the process
  • Eliminates need to invest in expensive facilities, infrastructure and equipment
  • Allows rapid scalability
  • Streamlined production process and accelerated time to market for mRNA based products
  • Provide long-term cost savings
  • Third party service providers mostly have expertise in regulatory compliance

Recent years have witnessed the emergence of a large number of highly qualified service providers that assist in synthesizing and manufacturing mRNA, further advancing mRNA related product / process development and mRNA manufacturing process.

Recent Developments in mRNA Technology

  • In November 2023, Trilink Biotechnologies set up an Analytical Sciences Center of Excellence to expand its comprehensive suite of mRNA specific analytical services; through the centralized hub, the company aims to advance the testing of nucleic acids, simplify mRNA drug substance testing and promote therapeutic development.
  • In November 2023, Merck expanded its newest biologics testing center in Shanghai, China.
  • In November 2023, Trilink Biotechnologies entered into a partnership with Intellia Therapeutics to supply products for mRNA manufacturing.
  • In September 2023, Merck set up two mRNA GMP manufacturing sites (drug substance) in Darmstadt and Hamburg, Germany; the expansion aims to complement the firms’ integrated mRNA service network with pre-clinical to commercial capabilities.
  • In May 2023, Aldevron announced the expansion of its mRNA production capabilities, with the inclusion of lipid nanoparticle (LNP) encapsulation and aseptic fill-finish capabilities.
  • In May 2023, Trilink Biotechnologies expanded its mRNA manufacturing capabilities to serve late-phase drug developers.

Concluding Remarks

Since the COVID-19 pandemic, mRNA based products have become one of the key areas of interest for researchers and drug manufacturers, across the globe. However, due to the complex mRNA manufacturing process, most of the companies are increasingly becoming reliant on third party service providers for their mRNA manufacturing operations. It is worth mentioning that various players are expanding their production facilities and capacities to meet the growing demands of their clients and stay at the forefront of innovation in this domain.

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https://www.rootsanalysis.com/reports/mrna-synthesis-and-manufacturing-market.html