Pioneering nucleic acid breakthroughs for the world
Nucleic Acid Insights 2024; 1(1), 37–41
What are you working on right now?
RL: I am currently working on quite a few things. Dan Anderson, a Professor of Chemical Engineering at the Institute for Medical Engineering and Science at the Massachusetts Institute of Technology (MIT), and my former postdoc fellow, is my collaborator on work in lipid nanoparticles, including developing new types. We are also investigating ways to use AI to help better design lipid nanoparticles and target them to different cell types, as well as uncovering novel methods of administration such as delivery via inhalation.
I also work closely with Giovanni Traverso, an Associate Professor in the Department of Mechanical Engineering, on the oral delivery of nucleic acids. And I am working with Ana Jaklenec on a variety of things, including ways of delivering nucleic acids via microneedles. In addition, Ana and I are developing portable 3D printers to produce microneedles in a globally accessible way, and finally, we are working on ways to better stabilize mRNA.
Can you give us your high-level summary of the current state of the art in the nucleic acids-based prophylactic and therapeutic vaccine spaces—and its limitations?
RL: It is remarkable to think about what has happened with mRNA vaccines over the past few years. Today, they can certainly be made rapidly and in a way that works very effectively—a standard flu vaccine might be 40–50% effective, but we see that mRNA vaccines can be as much as 94% effective in the case of Moderna’s COVID-19 vaccine. The state-of-the-art in that sense has taken a giant leap forward. Furthermore, before the pandemic, we had never seen vaccines being approved in less than a year from the start of development.
That being said, I think there are many improvements still to be made to mRNA vaccines. I would like to see the vaccines having a greater durability of response depending on the disease. You also want to see better tolerability—even though the side effects have been exaggerated by some (in the sense that according to the published literature, the mRNA vaccines have fewer side effects than the standard flu vaccines) we would someday like to see no side effects at all. Vaccines classically have been one of the safest ways to do things in healthcare. I would also like to see the field leverage other routes of delivery, including pulmonary and nasal delivery.
The same is true for DNA vaccines; we also want to see those become safer and more effective.
As the field strives to get beyond the liver in terms of targeted nanoparticle-enabled drug delivery, what do you view as the most promising approaches and target cells/tissues in this regard, and why?
RL: It depends on the type of nucleic acids being used. For many nucleic acids—namely those that are small enough, such as siRNA—you may not need nanoparticles for delivery. Instead, you may be able to modify these and bind them to something to improve their stability. This is something that Dan and I have worked on for siRNA. However, if a nanoparticle is required for delivery, then the approach taken will depend on what you are trying to do and which nucleic acids are being used. In our work, we have looked at targeting the heart, immune cells, and the brain.
It is possible to get these drugs past the liver, as there are ways to disguise them. The problem is then getting them to other places in the body. One of the keys for me that we have been working on is finding new receptors in other cell lines. Dan and I have been collaborating on some work with other targets. By identifying new receptors and specific tissues, there will be more opportunities to reach different and novel targets moving forward.
Looking to the future, what will be some important next steps or new directions in innovation in nucleic acid delivery for you?
RL: Many areas of study could prove useful, such as trying to introduce nucleic acids through less invasive routes. As mentioned earlier, if we could better stabilize nucleic acids and change the duration of these medicines, that would be valuable.
For vaccines, other routes of administration such as the dermal route or the nasal route will require different formulations. Over the years, our lab has worked on delivering things through just about every route in existence, including the eye, the nose, the lungs, the vagina, and the skin. We are continuing our work on expanding these delivery routes. Looking at it historically, every single one of those routes has been important for some specific molecules. Hopefully, cancer vaccines will be an area to watch in 2024.
On that topic, as a co-Founder of Moderna, you must have been particularly encouraged by the recent promising data for mRNA-4157/V940 in combination with Keytruda—what is your vision for the impact that nucleic acid vaccines can have in the therapeutic setting, both in cancer and beyond?
RL: The 3-year follow-up data for melanoma treatment with Moderna’s mRNA-4157/V940 in combination with Keytruda was recently released, and the findings have been nothing short of spectacular. Data continue to show an improvement in recurrence-free survival and a reduction in risk of recurrence or death of 49% compared with Keytruda monotherapy.
Keytruda is an effective drug on its own, so seeing improvements of this scale is excellent. The hope is to use this kind of vaccine in as many cancers as possible, although I do not see nucleic acid vaccines as being limited to just cancer. Any disease could be a target. Respiratory syncytial virus vaccination is one target on the immediate horizon for Moderna. The pipelines from Moderna and other companies are applying nucleic acid vaccines to many, many different diseases.
As a pioneer in the field, do you have a message for new arrivers in the rapidly expanding space of nucleic acid delivery?
RL: Looking back at my career, we were the first to develop delivery systems for nucleic acids, back in the mid-1970s. When we first looked to do that, people did not believe that it could be achieved. Many people said that delivering large molecules with tiny particles was impossible. When I give commencement speeches today, I tell the young people to dream big dreams. Dream things that you hope will change the world. If you do that, you should expect a lot of criticism, but don’t give up easily. This has been key in my own life and work.
Lastly, what are some key priorities for your work over the fore-seeable future?
RL: One of my biggest goals is to continue the work we have been doing in collaboration with the Bill & Melinda Gates Foundation to develop accessible medicines for the developing world. In addition to the microneedle patches I mentioned earlier, we have also developed so-called self-boosting vaccines. This is work conducted in collaboration with Ana Jaklenec—we have been working on a way to give one injection in circumstances that may currently require multiple injections. This means that patients would not need to come back for a second, third, or fourth injection, thus increasing compliance.
We are working on things across the board that will not only be as good or better than what currently exists, but that will also be cheaper and easier to use. The focus on improving both patient compliance in general and the ability to manufacture and deliver these products to patients on a truly global basis are cornerstones of these activities. Drug delivery in nucleic acids and many other molecules has made a tremendous impact on healthcare to date—the more we can do to enable the developing world to feel this impact, the better. The Gates Foundation has been very helpful in working to achieve this goal.
Robert Langer is one of eight Institute Professors at the Massachusetts Institute of Technology (MIT); being an Institute Professor is the highest honor that can be awarded to a faculty member. He has written over 1,500 articles, which have been cited over 414,000 times; his h-index of 320 is the highest of any engineer in history and the second highest of any individual in any field. His patents have licensed or sublicensed to over 400 companies; he is a cofounder of a number of companies including Moderna. Langer served as Chairman of the US FDA’s Science Board (its highest advisory board) from 1999–2002. His over 220 awards include both the United States National Medal of Science and the United States National Medal of Technology and Innovation (he is one of three living individuals to have received both these honors), the Charles Stark Draper Prize (often called the Engineering Nobel Prize), Queen Elizabeth Prize for Engineering, Albany Medical Center Prize, Breakthrough Prize in Life Sciences, Kyoto Prize, Wolf Prize for Chemistry, Millennium Technology Prize, Priestley Medal (highest award of the American Chemical Society), Gairdner Prize, Hoover Medal, Dreyfus Prize in Chemical Sciences, BBVA Frontiers of Knowledge Award in Biomedicine, and the Balzan Prize. He holds 42 honorary doctorates, including those from Harvard, Yale, Columbia, and Northwestern universities, and has been elected to the National Academy of Medicine, the National Academy of Engineering, the National Academy of Sciences, and the National Academy of Inventors.
Robert Langer PhD
David H Koch Institute,
Massachusetts Institute of Technology
Authorship & Conflict of Interest
Contributions: The named author takes responsibility for the integrity of the work as a whole, and has given their approval for this version to be published.
Acknowledgements: Photo source: Bob QE Prize© 2015 Queen Elizabeth Prize for Engineering Foundation
Disclosure and potential conflicts of interest: Langer R received support for the present manuscript from Combined Therapeutics, Evox Therapeutics, Geneleap Biotech, Hopewell Therapeutics, Marble Therapeutics, and Moderna.
Funding declaration: The author received no financial support for the research, authorship and/or publication of this article.
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Copyright: Published by Nucleic Acid Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.
Attribution: Copyright © 2024 Langer R. Published by Nucleic Acid Insights under Creative Commons License Deed CC BY NC ND 4.0.
Article source: Invited; externally peer reviewed.
Revised manuscript received: Jan 31, 2023; Publication date: Feb 2, 2024.