Uniting science to confront intractable diseases

Yokota I’ve always liked physics and chemistry since I was a child. After much thought, I chose to become a doctor. While working as a student and resident doctor in a medical setting, I learned that there were many intractable and rare diseases in the world, and that there were patients who died while suffering from their illnesses. I really wanted to help patients be free from pain and suffering, not only through medicine but also by drawing on the power of science and engineering, which I had always liked. So, I decided to become a neurologist, someone who treats diseases of the nervous system and muscles, including the brain, spinal cord, and peripheral nerves.

A person who has developed dementia no longer be aware of their condition, but the family has to look after the person for a whole decade or more, so I empathize with the family’s mental anguish. On the other hand, if a person has an intractable disease such as Parkinson’s disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), or muscular dystrophy, the situation is the complete opposite, as the person is unable to move a single muscle, but is fully conscious and in constant pain. As a doctor, I fully understand the situation, but there was nothing I could do to help the patients at that time. Such a state continues for 10 or 20 years. In order to treat these brain and nerve diseases, it is necessary to deliver drugs to the brain. However, during the 1980s-1990s, there was no way to treat such diseases, and we could only “sit with” patients as their illnesses progressed. Around 2000, the genes that cause hereditary neurological intractable diseases were finally starting to be discovered, and I, who had just returned from studying abroad in the United States, thought, “That’s it! Let’s use this discovery to promote the research and development of treatments.”

Yokota At the time, it was generally accepted that drug discovery was the job of pharmaceutical companies, and doctors assumed that their job was to use finished drugs in treatment. However, I thought that my mission, as a doctor who loves physics and chemistry, was to create new drugs using the various technologies possessed by pharmaceutical companies based on research results obtained by doctors in a clinical setting, such as the mechanisms of onset of intractable diseases, and to deliver them to patients.

In the United States, a type of nucleic acid drugs*¹ called antisense nucleic acids*², a new type of medicine, have been developed since the 1990s, and the development of small interfering RNA (siRNA)*³ has progressed since the 2000s. Large-scale investments had already been made, and there was intense competition in development. This was when I turned my attention to researching applications of siRNA. This field was led by the American biotech company Alnylam, which was working with Pfizer and Takeda Pharmaceuticals to develop new drugs. However, when Pfizer pulled out in 2011 with Takeda also withdrawing thereafter, I felt that it was completely hopeless. I even considered giving up at one point, but then I made up my mind and decided to create my own nucleic acids from scratch. I came up with the idea of DNA/RNA heteroduplex oligonucleotide*⁴ on a plane to Osaka, a major cultural and economic hub in Japan, to consult with Dr. Satoshi Obika, a leading expert in this field at Osaka University. Soon after arriving at the airport, I met Obika and we got carried away discussing molecular structure, and before I knew it, it was already midnight.

I would say that the idea of the DNA/RNA heteroduplex oligonucleotide is an application of the method of combining delivery ligands with antisense nucleic acids. As a neurologist, I had always felt that there was a high possibility of saving patients if we could deliver drugs to the brain. The idea came to me while I was trying to find a way to penetrate the blood-brain barrier — the barrier that prevents substances from being transported from the blood to the brain tissue — which was considered to be unfeasible. I was skeptical about its effectiveness at first, but when I conducted experiments involving animals, I was surprised to see that drugs passed through the blood-brain barrier and showed medical benefits. We also discovered that the double-stranded structure of the DNA/RNA heteroduplex oligonucleotide is biologically and uniquely recognized within the cells, and has its own transport mechanism.

Yokota The DNA/RNA heteroduplex oligonucleotide has a double-stranded structure formed by the complementary binding of DNA and RNA strands. Since it is highly stable and safe and can be involved in various biological processes, it plays an important role in regulating gene expression and is also used in molecular biological research. In addition, it made it possible for the first time to control the genes of organs other than the liver through systemic administration, which had been a major problem in the clinical application of nucleic acid drugs. Thanks to these characteristics, the DNA/RNA heteroduplex oligonucleotide is recognized as more than just an application of antisense nucleic acids. It is regarded as a nucleic acid drug with modalities different from conventional ones, and has gained recognition from chemists and pharmaceutical companies globally.

Yokota Science Tokyo is focusing on middle molecule drug discovery with nucleic acids and peptides as a research area in which the Institute will lead the world. We will promote research and development of next-generation middle molecule drugs, provide personalized healthcare especially to patients with intractable diseases, rare diseases, and ultra-rare diseases, and create new drugs. We will also work on its application for common diseases. Furthermore, we are aiming to develop preventive medicine using this technology, and to create a society where more people can maintain their health. In order to promote systematic research and development to the best of our ability, we established the Middle Molecule Drug Discovery Consortium. The organizations at the heart of the consortium are the NucleoTIDE and PepTIDE Drug Discovery (TIDE) Center of the former Tokyo Medical and Dental University (TMDU) as well as the Middle Molecule IT-based Drug Discovery Laboratory (MIDL) of the former Tokyo Institute of Technology (Tokyo Tech). We will lead the development by bringing together cutting-edge technologies and knowledge held by not only these two former universities but also all universities conducting research in this field and pharmaceutical companies developing new drugs, and integrating these technologies. We will also provide a platform for sharing knowledge and promote educational and promotional activities through the consortium to take an important step forward in opening up the future of healthcare.

Yokota First of all, I want to take the opportunity of the university integration to study chemistry, which I wanted to do when I was young. The power of chemistry cultivated at the former Tokyo Tech is important for future drug discovery.

I was really surprised. What we did is to slightly manipulate the small molecules and the atoms within the molecules. If you change one of the atoms in the nucleic acid, the nature of the entire nucleic acid changes completely. That’s how you make an artificial nucleic acid. Rather than prioritizing molecules that we humans naturally have, we create molecules that we don’t have. This is possible with middle molecules. To achieve this, we definitely need the power of chemistry.

By integrating the approaches of AI design, chemical synthesis, advanced measurement, and AI toxicity prediction, which have been promoted mainly by the MIDL of the former Tokyo Tech, the DDS technology of the middle molecular DNA/RNA heteroduplex oligonucleotide and mRNA as well as peptide technology using structural physiology of the TIDE Center, and the medical and life sciences knowledge of the former TMDU, we will be able to develop new middle molecule drugs more efficiently and effectively. This integration will unify the flow from basic research to clinical application and the development of preventive medicine, making it possible to deliver research results promptly to patients and medical settings for preventive care.

Yokota Middle molecule drug discovery will dramatically advance the treatment of intractable and rare diseases by acting directly on genes, which was difficult with conventional treatment methods. This new treatment will help many patients who had no options before. For example, patients currently have to receive an injection with a long needle in their back called lumbar puncture — which is painful and needs to be done many times for each treatment. If the medicine could be administered subcutaneously or orally, that would be very good for everyone. Furthermore, the development of personalized healthcare will enable us to provide optimal treatment for each individual, maximizing the treatment effect while minimizing side effects.

Middle molecule drug discovery is also a technology to expand the possibilities of new treatments. In addition to the development of new treatments, it also has great potential for developing preventive medicine. As we have new ways to prevent the onset of illness, we will be able to maintain good health, which will also lead to a reduction in medical costs for society as a whole. We will thus continue to strive to create new value together with society, while fulfilling the mission of Science Tokyo, that is “Advancing science and human wellbeing to create value for and with society."