Coming to you LIVE from the 3rd annual RNA Symposium: Advancing RNA Bioscience into Medicine. Follow us on Twitter or the tag #umichrna!

Live blogger: Whit Froehlich. Editor: Sarah Kearns.

Melissa Moore, Ph.D., is currently the Chief Science Officer at Moderna Therapeutics, having previously been on the faculty at the University of Massachusetts as Professor of Biochemistry & Molecular Pharmacology and Eleanor Eustis Farrington Chair in Cancer Research with a concurrent appointment as Investigator at the Howard Hughes Medical Institute. Her work ranges widely in RNA, currently focusing on pre-mRNA processing for medicinal applications. 

She starts with a few brief examples of drugs developed over the past 80 years, noting that biologics, therapeutics that have a biological structure, have grown to account for $180 of $600 billion spending on medications. These contrast with traditional (“small-molecule”) drugs, which contain within a single small molecule both a dianophore (localizing portion) and pharmacophore (active portion), by including more distinct and larger such portions. This increases the complexity and challenge of development. And drug development currently takes 12 years (and $2.5 billion)!

Differences between small-molecule and biologics as drug therapies. Image Source.

Each portion of the central dogma has been represented by biologic therapies: 400 protein therapies, 40 RNA therapies, and 5 DNA therapies. But that’s not very much – there’s a lot more to come!

The use of mRNA as a therapy was described back in the early 1990s and is used to target diseases before protein production. As such they are considered less dangerous than editing at a gene level. Further, they might be tolerated better by the human body than attempts to use recombinant protein therapies. However, there are some issues in administering RNA therapies.

Typically therapeutics are most effective if they are delivered directly, but mRNA is really big! At 1500-3000 bp, it has 10x the weight of the protein it encodes. This makes it really hard to get it where we’d want it in the cell. Additionally, the body has defense mechanisms as a part of its immune system. Key elements of the innate immune system are the receptors TLRs and RLRs that have evolved to work against exogenous mRNAs, usually encountered by the body in the form of viruses. Finally, you can’t just get the mRNA in – you’ve also got to get the ribosome, the complex that takes mRNA and transcribes it into protein, on board with translating the mRNA into the protein with the final intended effect.

A lot of design has to go into the mRNA therapies to avoid the immune system and making sure there’s enough protein product. Image Source.

Moderna and other companies have been working on these challenges because the potential is large. One part of this work is in siRNA with modified bases, which has been demonstrated to evade TLRs, but (with one exception) it hasn’t been able to engage the ribosome effectively. Now, sometimes it works to just inject “naked” mRNA into muscle with resulting protein translation – an upcoming drug in the works between AstraZeneca and Moderna is a formulation of VEG-F mRNA for intracardiac application in myocardial infarction patients (data from pigs are shown; currently in phase 2 clinical trials). In many cases, however, this technique does not sufficiently address the size problem.

For other cell types, and for systemic delivery, mRNA needs a delivery mechanism. The mechanism currently employed is a lipid delivery system composed of lipid nanoparticles forming an amino-lipid envelope. One such example of this system has been developed at Alnylam using MC3 to deliver other types of RNA treatments. Moderna is building on these efforts because mRNA has a much greater need for these encapsulations than siRNA. Dr. Moore shows that using Moderna’s lipid nanoparticles, mRNA tagged with a fluorescent tag is localized to the liver in a mouse model, as demonstrated by a bright glow in their livers. This shows promise for the application of specific and localized therapeutics.

Vaccine development, in particular, is a focus of her research because viruses are known to hijack the transcription system. But vaccine development takes quite a long time because we’re fighting the pace of evolution with slower tools, especially with influenza. If we were able to base a vaccine directly on the genetic code of the target organism, we could more rapidly produce an appropriate vaccine. Hence mRNA is a promising approach for a more responsive flu vaccine.

Another disease presenting an even more daunting challenge is CMV, a disease that currently has no vaccine or treatment. In particular, the CMV virus has a pentamer that hides behind a similar sequence, and so has thus far resisted efforts to develop a protein-based vaccine. One more disease currently being targeted is Zika virus, which demonstrates a rare case of acceleration of the drug timeline – the first construct was ordered in December 2015, and the first vaccine was in humans in December 2016.

Oh, and Moderna is big! Now over 600 employees. Big advances and one of the top medical research companies, now hiring!


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