The last session scheduled for the fortnight-long 2022 Tang Prize Masters’ Forum series was held on September 28 at National Tsing Hua University, where 2022 Tang Prize Biopharmaceutical Science laureate Dr. Pieter Cullis bedazzled the audience with a talk on “Lipid Nanoparticles, Gene Therapy and the Covid-19 mRNA Vaccine.” President of National Tsing Hua University Dr. W. John Kao graciously took on the job as the moderator. Among the experts on the discussion panel were Dr. Cheng-Hsun Chiu, vice superintendent of the Division of Pediatric Infectious Diseases at Linkou Chang Gung Memorial Hospital, Dr. Han-Chung Wu, director of the Biomedical Translation Research Center at Academia Sinica, and Dr. C. Grace Yeh, chairman and CEO of Onward Therapeutics SA.
Dr. Cullis spearheaded the technology that allows lipid nanoparticles (LNPs) to package nucleic acid-based drugs and deliver them efficiently to target cells or organs. It is an integral part of the medical achievement represented by mRNA vaccines and therapeutics. Such an exciting topic saw the venue packed with hundreds of students and faculty members of the host university, researchers from other institutions, and representatives of several biopharmaceutical companies. The Tang Prize Foundation also livestreamed the forum on both its Chinese and English channels for those unable to attend in person.
In his presentation, Dr. Cullis presented an overview of his research career that has spanned over five decades, and ran the audience through the development of LNP delivery systems that took him nearly 30 years. It all began in 1972 when the interest in membrane lipids promoted Dr. Cullis to switch from physics to biochemistry. After years of research and collaboration with many scientists, his team first synthesized liposomes and kept optimizing their functions so as to allow them to deliver drugs with different properties, leading to the eventual creation of LNP technology. Dr. Cullis explained that gene therapies employing genetic drugs have the potential to cure most diseases. However, sophisticated delivery systems are required to enable the medical use of nucleic acid polymers as they are quickly broken down in biological fluids and cannot penetrate into target cells even if they arrive at target tissues. LNP technology is increasingly enabling the clinical potential of genetic drugs. Clinical validation of this approach was achieved by the approval of Onpattro by the US Food and Drug Administration in 2018. Onpattro consists of LNPs containing siRNA that silences the TTR protein in the liver (in hepatocytes) following intravenous administration, thereby making it a curative therapy for transthyretin-induced amyloidosis (hATTR), previously an untreatable and fatal disease. After using the story about Onpattro to illustrate the historical development of LNP systems, Dr. Cullis then described how related technology is being employed to enable many mRNA-based gene therapy drugs. A notable example of the success of this approach is the development of the LNP Covid-19 mRNA vaccines. Until the end of 2021, nearly 3 billion doses have been produced globally.
Following Dr. Cullis’ edifying speech was Dr. Kao’s question about what gave Dr. Cullis the staying power to persevere with his research on LNPs for fifty years. In his response, Dr. Cullis noted that one key element is “the fascination with basic problem,” saying that even after studying LNPs for several decades, he still feels that he has barely scratched the surface of the properties of these molecules and thus remains deeply fascinated until today. Dr. Wu complimented Dr. Cullis on his inspiring research work which involves the fields of physics, chemistry and biology and which successfully translated LNP technology from an asset of the academic community to that of the biotech industry. He also wondered if the cytotoxicity of LNPs has anything to do with the common side effects of mRNA vaccines. Dr. Cullis replied that we needed PEG lipids there to stabilize the size of these particles in storage and the jury was still out there on how we might counteract the allergic reaction to these lipids. As for the issue of cytotoxicity, the closer the ionizable lipids get to neutrality, the more toxic they become. If you can hold them to the range below pH 6.4, they seem to be pretty well tolerated. So he is optimistic that the toxicity of these lipids is something we can control.
Making her comments, Dr. Yeh first reflected on the difficulty of transforming a research outcome in a laboratory to an application in the biomedical industry. She then asked about the limitations lipid formulations could face, even though gene therapy has great potential for treating many diseases. Dr. Cullis mentioned that to get nanoparticles across the many barriers in our body was a real challenge and we had a long way to go before knowing how to get them into the brain from an IV injection. On a bright side, they transfect liver cells quite effectively. He agreed with Dr. Yeh that the mRNA approach, in comparison with the DNA one, is relatively safe and easier to control, because, unlike ramifications associated with genome editing technology, RNA-based drugs don’t get into the nucleus, so they don’t really affect the genomic material. Another question posed by Dr. Yeh was about the different factors that would determine which formulation Dr. Cullis uses for a particular project. In his answer, Dr. Cullis pointed to the complexity of biology, explaining that “if your delivery system is not well
characterized, you aren’t making exactly the same thing each time. Then the result can get incredibly confusing.” Thus, the first thing that should be concentrated on is to make sure you know the size of the system, the amount of drug in it, and that it is highly efficient. In addition, we should not only look at the potency of a drug when measuring its toxicity, but should try to maximize its therapeutic index. “One problem with looking at animal models and translating that to the clinic is that you very often would lose a lot of your therapeutic window,” Dr. Cullis added.
Dr. Chiu wanted to know how LNP technology can be employed to treat cystic fibrosis. Dr. Cullis thinks that “IV is probably in the end the technique that gets us there.” Hopefully in the future there will be a system that can circulate in the body for much longer, and we should “try and figure out how to turn things on and off in particular locations. That can be done theoretically by some molecular biology approach. Perhaps carrying along some genes with lipid nanoparticles that we can turn on and off using external radiation, x-rays, laser or RF,” Dr. Cullis predicted.
One of the audience’s questions concerned how to overcome challenges, about which Dr. Cullis emphasized that team work was the source of higher motivation. People working together can lift each other’s spirits when setbacks strike and make the journey of research and innovation more enjoyable. Moreover, keeping a team together also helps in terms of securing funds for the development of new drugs. Facing all kinds of queries from the panelists and the audience, Dr. Cullis was always ready to share his experience and knowledge, be honest about the riddles that he still can’t solve, and never cease to be positive. He especially pointed out that he often found himself learning a lot from the experiments that didn’t go the way he had expected. Therefore, he suggested that we don’t get locked into our own hypothesis, because the unexpected can “lead you onto a new path.” Finally, Dr. Kao concluded the forum by reminding us that we are learning something new every day and so the most important thing is to stay passionate and curious.
To watch the forum again, go to: https://www.youtube.com/watch?v=LoK94h9QFIM&t=4s
The 2022 Tang Prize in Biopharmaceutical Science was awarded to three heroes behind the development of SARS-CoV-2 mRNA vaccine, Drs. Katalkin Kariko, Drew Weissman, and Pieter Cullis, “for the discovery of key vaccinology concepts and approaches, leading to successful development of mRNA-based Covid-19 vaccine.” While Dr. Kariko and Dr. Weismann found a way to reduce the immunogenicity of mRNA, Dr. Cullis is credited with designing lipid nanoparticles for the delivery of mRNA vaccines. A pioneer developer of lipid nanoparticles and a professor at the University of British Columbia, Dr. Cullis is also a leader in the study of the structure and function of cell membranes at the molecular level for the development of effective therapeutic agents. A great percentage of FDA-approved or emergency use of lipid nanoparticles have relied on the technology he created.
About the Tang Prize
With the advent of globalization, mankind has been able to enjoy the convenience brought forth by the advancement of human civilization and science. Yet a multitude of challenges, such as climate change, the emergence of new infectious diseases, wealth gap, and moral degradation, have surfaced along the way. Against this backdrop, Dr. Yin drew on his experience of investing efforts in education for more than two decades and established the Tang Prize in December 2012. It consists of four award categories, namely Sustainable Development, Biopharmaceutical Science, Sinology, and Rule of Law, aiming at responding to the unique problems humanity faces in the 21st century. Every other year, four independent and professional selection committees, made up of many distinguished international experts and scholars, including Nobel laureates, choose from a pool of nominees who have influenced and made substantive contributions to the world, regardless of ethnicity, nationality or gender. A cash prize of NT$50 million (approx. US$1.7 million) is allocated to each category, with NT$10 million of it (approx. US$ 0.35 million) designated as a research grant to the laureate to support relevant educational projects. It is hoped that more people with professional knowledge and skills will be motivated to address mankind’s most urgent needs in this century, and to become leading forces behind the development of human society through their outstanding research and active civic engagement.