{"id":273,"date":"2021-03-01T18:00:20","date_gmt":"2021-03-01T23:00:20","guid":{"rendered":"http:\/\/blogs.shu.edu\/ihsl\/?p=273"},"modified":"2021-03-01T18:20:55","modified_gmt":"2021-03-01T23:20:55","slug":"mrna-technology-a-shot-in-the-arm-for-development-of-new-drug-therapies","status":"publish","type":"post","link":"https:\/\/blogs.shu.edu\/ihsl\/2021\/03\/01\/mrna-technology-a-shot-in-the-arm-for-development-of-new-drug-therapies\/","title":{"rendered":"mRNA Technology: A Shot in the Arm for Development of New Drug Therapies"},"content":{"rendered":"

As millions the world over receive mRNA-based vaccinations for COVID-19, there is hope that the virus and its attendant wanton destruction may soon be in our collective rear view mirrors. Other vaccine approaches, for example employing viral vectors, are making their way into the armamentarium of anti COVID-19 treatment options \u2013 the news just keeps getting better. The focus here is on mRNA technology \u2013 how did we get to this point, and what does it mean for the future?<\/p>\n

\"mRNA
Image Source: MIT News<\/a><\/figcaption><\/figure>\n

The central dogma of molecular biology – loosely defined – states that DNA instructs mRNA creation, which directs protein synthesis. Ultimately, of course, it is the protein or enzyme created that is the molecule missing or defective in disease or needed to create immunity. DNA\/gene-based therapies have existed for some time and recent advances have begun to overcome early technical problems encountered. The use of protein biologics \u2013 molecules produced in living cell \u201cfactories,\u201d have also emerged as a viable option to treat protein\/enzyme deficiencies or to introduce specifically designed functional antibodies. However, as a protein biochemist who has developed protocols for purifying enzymatically active protein biologics, I can assure you the process is exquisitely complex, time consuming, and costly. The approach can and has worked \u2013 it is simply a matter of committing the time and resources to empirically determining\/optimizing the purification protocols.<\/p>\n

Another option has emerged – specifically, the development of mRNA technologies as a mechanism to induce protein\/enzyme expression. Again, as pointed out above – it is not that the role of mRNA in protein synthesis was unclear, rather, there were technical problems attendant to the approach. Let\u2019s consider some of these previous limitations and how they were overcome to allow mRNA to be an efficient messenger of protein synthesis in humans.<\/p>\n

mRNA is exquisitely unstable. RNAases \u2013 enzymes which break down mRNAs, are very efficient and ever present. mRNA will not enter cells, and if they could be transported, their mere presence often elicits an immune response. Couple this with relatively low protein yields from the cell\u2019s translation processes \u2013 and the need for repeated dosing is manifest. So, what has changed?<\/p>\n

First, Karik\u00f3 and coauthors showed that employing specifically modified nucleosides in the design and synthesis of an mRNA molecule would render it far less immunogenic.1<\/sup>\u00a0A great first step! Next, the sequence of the mRNA coding region (the area that encodes the information for the protein itself) would take advantage of what was known about (protein) translation. That is, some codons (~mRNA sequences that encode specific amino acids) are expressed more efficiently than others \u2013 resulting in greater overall protein yields. Recall that most amino acids are encoded by more than one codon, that is, the genetic code is degenerate. Detailed structural analyses of mRNAs also yielded new information about the importance of 5\u2019 and 3\u2019 untranslated regions in terms of the molecule\u2019s overall stability and translational efficiency. A more complete understanding of mRNAs\u2019 5\u2019 cap and 3\u2019 poly (A) tail served to further extend the ability to preserve the molecule\u2019s integrity.<\/p>\n

Next, it was necessary to design a delivery system \u2013 a mechanism that would both protect the mRNA molecule, as well as assure its entry into cells. Many approaches were tested \u2013 lipid nanoparticles emerged as an efficient option. Once encapsulated and introduced into tissues, the mRNAs are internalized into cells by endocytosis \u2013 basically an engulfment of the lipid vesicle by the cell\u2019s plasma membrane. Once inside the cell \u2013 the nascent endosome degranulates and the mRNA molecule is able to emerge into the cytoplasm and begin directing protein synthesis. The cell itself thus makes the protein.<\/p>\n

Where does the technology go from here? The answer – quite simply, is that mRNA therapy could potentially be a suitable approach to treat many human diseases. Single enzyme deficiencies constitute a large class of lysosomal storage diseases (e.g., Tay-Sachs or Inclusion-cell (I-cell)), inherited metabolic diseases (e.g., Gaucher or Hunter syndrome), and peroxisomal diseases (e.g., acyl-CoA oxidase or D-bifunctional protein deficiency). Arginase deficiency and cystic fibrosis (caused by the dysfunctional cystic fibrosis transmembrane conductance regulator molecule) are two additional proteins whose missing or defective activities are associated with disease and whose replacement is being sought through mRNA therapies. Designing and synthesizing appropriate mRNAs is relatively straightforward, as is lipid nanoparticle encapsulation. Cold chain handling of the resultant therapeutic remains a requirement \u2013 but what a small price to pay for what could be life-changing medicines. It would not be inappropriate to say \u201cthe sky is the limit\u201d with respect to the potential of mRNA-based protein\/enzyme replacement therapeutics.<\/p>\n

SRT \u2013 February 2021<\/p>\n

Reference:<\/strong><\/p>\n

[1] K. Karik\u00f3, M. Buckstein, H. Ni, and D. Weissman, Immunity<\/em> (2005) doi: 10.1016\/j.immuni.2005.06.008<\/a>. PMID: 16111635<\/p>\n","protected":false},"excerpt":{"rendered":"

As millions the world over receive mRNA-based vaccinations for COVID-19, there is hope that the virus and its attendant wanton destruction may soon be in our collective rear view mirrors. Other vaccine approaches, for example employing viral vectors, are making their way into the armamentarium of anti COVID-19 treatment options \u2013 the news just keeps … Continue reading “mRNA Technology: A Shot in the Arm for Development of New Drug Therapies”<\/span><\/a><\/p>\n","protected":false},"author":4241,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_monsterinsights_skip_tracking":false,"_monsterinsights_sitenote_active":false,"_monsterinsights_sitenote_note":"","_monsterinsights_sitenote_category":0,"footnotes":""},"categories":[1],"tags":[58,70,71],"class_list":["post-273","post","type-post","status-publish","format-standard","hentry","category-terlecky","tag-covid-19","tag-mrna","tag-therapies"],"_links":{"self":[{"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/posts\/273","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/users\/4241"}],"replies":[{"embeddable":true,"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/comments?post=273"}],"version-history":[{"count":4,"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/posts\/273\/revisions"}],"predecessor-version":[{"id":279,"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/posts\/273\/revisions\/279"}],"wp:attachment":[{"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/media?parent=273"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/categories?post=273"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/blogs.shu.edu\/ihsl\/wp-json\/wp\/v2\/tags?post=273"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}