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    (Podcast) mRNA Therapies & Vaccines: Hopes of Applicability to a Wide Range of Diseases

    By ZAGENO Team - 10 minutes read

    Dr. Richard Wooster has had a distinguished career focused on cancer, genetics and pharmaceutical drug discovery and development. 

    Before joining Translate Bio, in 2019 as its chief scientific officer, Dr. Wooster held a number of leadership roles at Tarveda Therapeutics, GlaxoSmithKline, and is one of the founders of the cancer genome project at the Wellcome Trust Sanger Institute, where he discovered the breast cancer susceptibility, gene BRCA2.

    Dr. Wooster has more than 100 peer reviewed articles and papers in scientific journals and we are very grateful that he's agreed to join us for this conversation. Richard, welcome to the podcast.

    Thank you, it's a pleasure to be here.

    Joining me and asking questions of Richard is Peter Grayson, a member of ZAGENO's science and data team. Peter's credentials include degrees in biomedical science and cancer from Newcastle University and his related research should make for a far more authentic discussion focused on science.

    Peter, thank you for joining us. 

     

    Thanks, Greg and welcome again, Richard. 

    Now, you've been a scientist for more than 30 years and in that time you've had a front row seat in many different environments and workplaces but recently you focus more on smaller organizations. 

    For you, what have been the key differences in terms of resources, communication, goals, and any other kinds of things you can think of?

    That's a great question. 

    All of these have been fantastic opportunities to learn, to gain insights from different perspectives with a common goal and that is how to help patients; how to use science in a way that you can make discoveries, whether that's through discovering genes that cause disease or discovering medicines that are designed to help patients get to that common goal. But in those different experiences there are different approaches to this that you can bring together. 

    So, for example, thinking about smaller organizations... that could really help in thinking how you focus your mind, what are the most important experiments? What are the most important questions you want to answer? And then how do you spend your time, your money most efficiently towards that? 

    There could also be an element of speed and decision making, where, in a smaller organization, you pull together the right people to review plans, review data, make decisions, and then move on to the next step. And of course, with what we do in science, it's always that cycle of, you have a hypothesis, you design experiments on how to test that, you review the data, you incorporate that data into your thinking, and then you iterate through that time and time again.

    ...in a smaller organization, you pull together the right people to review plans, review data, make decisions, and then move on to the next step.

    Larger organizations by their nature are going to be having more infrastructure, whether it's committees or meetings because you're looking to communicate as to get input across a far larger group. 

    Contrasting that to larger organizations, there can be a temptation to try and do everything or to try and do many different things and to dilute what you're doing to become less focused. Larger organizations by their nature are going to be having more infrastructure, whether it's committees or meetings because you're looking to communicate as to get input across a far larger group. 

    So, that's maybe a downside of larger organizations but a good side is actually the institutional memory. These organizations have seen in many different scenarios some which they've revealed to the world but others, which they keep internally as know-how of advantages that they have. And so that can be taking things that worked or things that maybe failed and so you're incorporating those into your thinking.  

    Institutional memory can work in a not so productive way, as well. When faced with a particular challenge, you say, we're going to do this experiment and when asked, why it's, this is the way we always do it. I think that can be, not optimal because we should really be thinking critically every time we become focused with a question, what's the best path forward on this occasion? 

    In totality, I would say this experience has created this larger menu of options that I could pull together, today. The first thing that comes to mind is if you walk into a restaurant and you sit down and there's this huge menu in front of you. As you start to look through the pages, you've tried some of the dishes maybe in this menu or maybe at other restaurants and some will go well together, you like them and you maybe pick them again.  And other dishes you say, I've tried this and it wasn't for me, it's not what I want. And there are yet some dishes which you've yet to try and maybe you will get to try in the future. But depending on the situation, is it a celebration? Is it a routine meal? Is it something different? And you can use that experience to go through the pages of the menu and choose what's appropriate for this particular setting. 

    So, I feel I've had a very fortunate set of experiences that have allowed me to pull that menu together. 

     

    I really liked that restaurant analogy. It's not one I've heard before, but it's something that I can relate to and agree with. 

    Focusing in on that, could you tell us more about Translate Bio and what your current experience is with this team of scientists, currently in the company?

    We're based in Lexington, Massachusetts, just outside of Boston and  were focused on discovering and developing mRNA-based therapeutics and vaccines. We're just over a hundred employees at the moment and might grow in the future. Both our scientists, but we're really everybody here is passionate about this tremendous potential of mRNA to treat diseases where there may be few or no options, today.

    mRNA therapeutics have an ability for us to think of targets, which maybe we couldn't be addressed with any other type of approaches, small molecules antibodies, for example.

    I think the mission is putting people first and it's how we do that with mRNA, therapeutics. So for example, our lead program...  we're now in an early phase 1/2 clinical trial with a treatment for cystic fibrosis.

    While there have been many advances in the treatment of cystic fibrosis, over the past few years, and that's been fantastic for many of these patients, there are still subsets of individuals with cystic fibrosis who gained very little benefit from some of the more recent advances.

    ...our work with Sanofi in discovering mRNA vaccines is really setting the stage for us...

    So, we are looking at how we can use mRNA to help those individuals and that comes to our clinical study. But beyond thinking of therapeutics, which, this will be a therapeutic for cystic fibrosis, thinking about how we protect people. In that sense, our work with our partner, Sanofi in discovering mRNA vaccines is really setting the stage for us there.

     

    So, talking about mRNA or messenger RNA, for those who don't come from a science background, as you've already mentioned, has a huge potential to revolutionize medicine but currently there aren't any therapies available on the market. 

    So, which research fields do you think would benefit most from mRNA therapeutics?  

    I think ultimately we could see mRNA therapeutics being applicable in a wide range of diseases. As you say, this is a new approach and new technology and so validating this is important to take us forward and gain confidence in the potential.

    The path that we've taken here with, for example, cystic fibrosis it's a known genetic disease and so we know the individual patients who have cystic fibrosis. The particular aspect of the disease is either a loss of the CFTR gene in those patients or mutations, which cause a seriously reduced amount of the CFTR protein.

    mRNA is that intermediary between our DNA, our genome, and then making proteins. What we have the ability to do is to make mRNA, to package that to deliver to the cells, and then support the cells, if you like, or allow the cells to restore the expression of that defective protein. 

    That's how we're looking to provide that benefit to the individuals. And we're doing this with a focus on pulmonary diseases, so diseases of the lungs. We're also developing mRNA vaccines for infectious diseases and that includes COVID-19 where we're working with our partner, Sanofi.

     

    Yeah,  there are a lot of  potential uses for mRNA in different research fields, as you mentioned but there are still many challenges that mRNA faces in the future. 

    What do you think are some of those challenges that prevent mRNA medicines from reaching critical trials, that is until recently?

    In some ways, this goes back to a number of years ago when I was in the lab and working with mRNA at the time. 

    It's an incredibly unstable molecule. The joke in the lab was if you have made some mRNA and it was in a tube don't even touch the tips that you might be using, or some of the instrumentation you might be using, because we can have RNA -  so enzymes - that degrade mRNA on our fingertips. It was so easy to contaminate that mRNA and to cause it to be degraded and disappear. 

    What we've done at Translate Bio is worked through both how we can make mRNA at a scale and a quality that you would want for a drug, essentially. And then how we protect that RNA so that it can be retained in that state that it needs to be able to make the proteins and then enabling the delivery of the mRNA, inside of the cell.

    What we've done at Translate Bio is worked through both how we can make mRNA at a scale and a quality that you would want for a drug, essentially. And then how we protect that RNA so that it can be retained in that state that it needs to be able to make the proteins and then enabling the delivery of the mRNA inside of the cell.

    When you think about mRNA, it's a charged molecule, it will not pass through membranes. And so we package the mRNA. It not only protects that, as we administer it to patients, but also facilitates the uptake into the cells, the release into the cytoplasm, where the ribosomes are going to "translate" that.

    The team has spent many years working on how to optimize those different components. It's really not been done before so it's exciting to be part of this wave of innovation, as we've been working towards this and now seeing the results of that coming out with our CF trial but also multiple other discovery programs, which we have ongoing.

     

    And it must be very frustrating to deal with mRNA when it's such an unstable molecule. It's very easy to degrade, and quite often you have to start over again.  I think that makes it hard to choose in which area to focus, when the molecule is so difficult to deal with. 

    You mentioned cystic fibrosis and other lung diseases and I wondered why Translate Bio decided to start in this area or if it was just the way that the research developed?

    We have certainly explored a number of different diseases and potential applications for our technology. While each comes with a slightly different perspective and challenge, to be resolved, and we've been making advances across many of those, for our cystic fibrosis program, for other programs, which we have in discovery, we actually deliver this by inhalation - so patients would be inhaling the mRNA. It will then almost get directly to the cells that are lining our lungs to be able to have that effect. So we are getting that direct delivery component.  

    That might sound simple but it's actually far more complex because our lungs are designed to protect us from the outside world, to protect us from bacteria or particles that we might inhale. And so we've worked on how we actually break through that barrier to be able to get inside of the cells to have that effect and certainly are excited by the data we're seeing, in that respect. But I think there's potential for additional paths that we could take in the future.

     

    Yeah, as you say, inhaling mRNA all sounds very simple, but that barrier between our lungs and our blood stream is obviously very complex for a reason and that is to protect us. So, overcoming that, obviously, poses a lot of potential problems so it's very exciting to hear that you've overcome that, with some recent breakthroughs. 

    Coming back to cystic fibrosis that you mentioned earlier, this disease is the result of a mutation of a single gene, which maybe makes it easy to target. Is that the case? Is it potentially a factor when you were choosing to start in this area?

    I think it's definitely a component because we know what the gene is that we're looking to target so that's a great starting point. And there are other, similar genetic diseases. 

    There's one, which we're very interested in called Primary Ciliary Dyskinesia. This relates to these tiny hairs, which actually line certainly the upper part of our lungs. These hairs beat in unison and draw mucus that's collected these bacteria, these particles, they draw that mucus up out of your lungs - so, pulling it out. And in Primary Ciliary Dyskinesia or PCD, these individuals have genetic mutations, which lead to defects in their cilia. Sometimes there were no cilia, sometimes they don't beat in unison.

    Imagine a comparison between a disco, where everybody's doing their own thing compared to a very structured dance where everybody is moving in the same direction. In the "disco cilia " they're all beating out of sync and so the mucus doesn't get pulled out to the lungs.

    So, here's another opportunity where mRNA can have that potential to introduce that defective protein and restore the function of those cilia - get them all dancing in unison. 

     

    I loved the metaphor that you use, it's great  that science can improve one's dancing, or at least the dancing of a cell. It's great to hear that it isn't just cystic fibrosis that this can be applied to in the pulmonary disease world and there are potentially other implications, there.

    Talking about wider applications. Do you think this mRNA technology could  target other diseases, outside the pulmonary disease world?

    It has broad applicability. Certainly an area of which we're interested in are a number of liver diseases. In this setting the mRNA, in its protective lipid nanoparticle, would be delivered intravenously. As that circulates through the blood, be taken up by the liver and, in the same way, the RNA being delivered into the cytoplasm and expressing proteins.

    I think what is exciting about the mRNA and maybe just getting into the types of proteins we can express really, we could express any protein that is going to provide benefit.

    I think what is exciting about the mRNA and maybe just getting into the types of proteins we can express... really, we could express any protein that is going to provide benefit. With our CF program, it's a transmembrane that is being inserted into the membrane as would a normal transmembrane protein. But we can make proteins which can get to the nucleus, which can get to the mitochondria, even secreted proteins and so there's really a broad spectrum of the type of proteins that we can make. 

    And beyond normal proteins, what we are also now exploring, is engineering proteins. So making subtle but rational modifications to the protein sequence, which we are exploring for their potential enhancement of the benefit that we want to make. But you could imagine making completely artificial protein constructs that you wouldn't necessarily see in humans from our genome. 

    I think what we always balance, as we make these new constructs, is what might be the downside of doing that and being very cautious in how we explore those and balancing that potential upside with, are these going to be tolerated?  What could be some of the downstream consequences, but I think yes, broadly a very interesting platform for us to develop further. 

     

    Yeah. It's always a case of weighing up the risks when looking into new areas in the body, especially with mRNA, which is such an influential yet, unstable molecule  So, I can appreciate that venturing there can be frightening and difficult but, it sounds like you have, as you say, a good platform, to look into these areas. 

    And, as we broadened our scope, here, about mRNA's capabilities, with the rise of COVID-19 - especially right now, do you think Translate Bio will look into vaccines more as a possible route for mRNA technology?

    Absolutely.

    In 2018, we started our partnership with Sanofi who are one of the leading vaccine companies in the world. This was initially focused on five infectious diseases. And as the COVID-19 pandemic started to emerge we thought about how we could play our part.

    We actually expanded that partnership with Sanofi, in March this year, to include the discovery of a vaccine for COVID-19. And then in June, this year, we actually expanded that even further to include all infectious diseases and really now excited about continuing to work with Sanofi around our vaccine work and the capability or the potential of mRNA vaccines for the future. 

    We actually expanded that partnership with Sanofi, in March this year, to include the discovery of a vaccine for COVID-19. And then in June, this year we actually expanded that even further, to include all infectious diseases

    I'm really excited to see how that progresses as I think many scientists across the world are. And I look forward to seeing any future developments.

     

    And that concludes part one in our conversation with Dr. Richard, Wooster.

    Check back soon for part two.

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