Shining Hope for Myotonic Dystrophy: A New Drug Discovery – Science View
Sato Mino is a patient with myotonic distrophe, a hereditary disease that still has no cure. It gradually causes the muscles throughout her body to grow weaker. Her son has also been diagnosed with the same condition. It is. Sato once held a key position at her local supermarket. She was also active as an actress in a theater company. But gradually her future options became more limited. At the moment there is no drug to treat myotonic drophe and no way to halt its progression. But now one position has opened the path forward. This is Professor Masayuki Nakamoi of Yamaguchi University. [Music] Now patients place their hopes in the drug discovered by Professor Nakamoi. I try hard to do my research to help a patient. This is a story of patients battling a disease and a doctor fighting by their side. [Music] Over the past few decades, medical advances have made it possible to treat many diseases. However, there are still numerous incurable conditions for which no cure has been found and no effective way to stop the progression of symptoms. Myotonus destroy is one such disease. It gradually weakens the muscles of the limbs and face while also increasing the risk of developing other serious conditions. Until now, no effective treatment has been found to stop its progression. But today, there’s a researcher bringing new hope to patients. His name is Professor Masayyuki Nakamuri of Yamaguchi University. Today, we’ll take a closer look at Professor Nakamuri’s efforts towards developing a treatment. Ube City, Yamaguchi Prefecture, once thrived as a company town built on the coal industry. 80 years ago, with some help from a local company, a school was established. That school eventually evolved into what is now Yamaguchi University School of Medicine. Hello. Oh, thank you for having us today. What does that mean? Oh, mas is a traditional greeting in the Yamaguchi dialect. That means welcome to Yamaguchi. Oh, that’s nice. Odas, that kind of has a very nice sound to it. Oh, yes. Uh, Yamaguchi is beautiful place and one of Japan’s hidden gems, I think. And here it’s not crowded like the big cities. And it really feels calm. Oh, there must be a great place to do your research then. Oh, yes, exactly. So, professor, you have dedicated many years to studying myotonic distrophe. This disease is not widely known, but can you tell us how many people are affected by it? So it’s difficult to know the exact number of the patients because some people with symptoms never see a doctor but it’s estimated that there are at least 10,000 in Japan and worldwide uh the number is thought to be at least a million. What inspired you to begin your research on this illness? uh after I become became a neurologist, I saw a lot of patients and realized that there was no treatment available and so it really hit me and I wanted to do something about it. So I started uh doing research while continuing my clinical work. So what exactly is a myotonic distrophe? Let’s take a look at an interview with a patient. In the Tohoku region, not far from the Pacific lies Tagajjo city, Miyagi Prefecture. It is home to Sato Mino who lives with myotonic distrophe. Though her symptoms worsen gradually, Sato carries a positive spirit, striving to live and manage her daily life. Oops. [Music] S first noticed a change in her body 25 years ago. Then eight years later, [Music] [Music] Myotonic distrophe is a disease caused by genetic abnormalities. Genes are built from sequences of four bases which together form the human body and its countless functions. In patients with myotonic drophe, a base sequence called CTG is repeated more extensively than in healthy individuals. When transcribed into RNA, the repeated sequence becomes CUG. The RNA bends into an abnormal shape like a hairpin. Then it begins to trap regulatory factors which are essential for keeping our bodies working smoothly. [Music] Because those regulators get stuck, they cannot perform their jobs. As a result, there’s a decline especially in muscle function. It can also affect other organs like the heart, brain, and eyes. [Music] In 2011, the great East Japan earthquake struck and Tagajjo city where Sato lived suffered extensive damage. Fore! Foreign! Foreign! Sato had no choice but to leave her job. She also offered the theater company leader her wish to step down from the troop where she had belonged to something she did for the love of it. This was S’s final stage appearance. [Music] Sato continues to carry hope in her heart that one day there’ll be a drug to cure her disease. [Music] So, Miss Su is living positively, doing her best, but it must be very difficult as the disease continues to progress without a cure. Oh, that’s right. So, Miss Sato puts a lot of effort into her daily life, uh, constantly making adjustments. Uh, but living with a condition that has no treatment is really tough for her and her family. It must be really challenging to restore genetic abnormalities. Yes. Uh for infectious diseases, uh you can take medicine to kill the bacteria and for cancer uh you can have surgery to remove it. However, even with current science, it seemed difficult to fix the problems at the genetic level. But you have found a clue to treating this disease, right? Oh yes. Uh we have found a drug that may uh effective for this disease and it’s in the clinical trial stage. The new drug take time to develop but uh in that time uh the disease uh keeps progressing. So we looked for uh something useful among existing drugs. Mhm. So if it’s an existing drug, you don’t have to wait for decades to check up on its uh efficacy or safety. Mhm. That’s right. Oh, that that is a great idea. Professor Nakamuri continues to see patients with myotonic distrophe even while conducting his research. [Music] Nakamoi wondered if he could somehow find a way to cure this disease. He investigated tens of thousands of existing drugs and compounds to find candidate substances. [Music] First, he selected those that could bind to RNA. There were about 1,000 in all. Then, he narrowed the list to those which the safety had been verified to a certain degree, leaving roughly 200. Finally, he filtered for those without serious side effects and are suitable for long-term use. [Music] From that process 20 compounds remained mainly among existing drugs. [Music] Professor Nakamuri added each of those 20 candidate substances to cells with myotonic distrophe and tested their effects one by one. The cells were cultured for two days. Then a special reagent that reacts specifically to the abnormal RNA that causes myotonic distrophe was applied. The slides were observed under a microscope. From that he discovered a drug that can block the activity of abnormal RNA. [Music] This is ariththroycin, an antibiotic that acts on RNA to stop bacterial growth. It has long been used to treat infections like pneumonia. [Music] Here is a microscopic image of cells without ariththramy. The red dots indicate abnormal RNA. In this next image, ariththramy had been added to the cells. The abnormal RNA dots in red had disappeared. Experiments were also conducted on mice showing symptoms of myotonic distrophe. This graph shows the percentage of normal RNA in healthy mice. The percentage is significantly lower in mice with myotonic distrophe. However, when ariththramycin was administered, the more amount it was given, the higher the percentage of normal RNA became. In this way, the therapeutic effect of ariththramy was confirmed at the level of animal experiments. [Music] Based on these findings, clinical trials on people were conducted at three hospitals. One of them was Ali National Hospital. The trials were led by Dr. Hiroto Takada who has long been involved in treating patients with myotonic distrophe. One of the participants was Fisher NO. Her daughter also has the same disease. [Music] A total of 30 patients took part in the trials in three different hospitals. They were divided into three groups. Some were given arythroyc while others were given a placebo or a dummy drug. But neither the patients nor the doctors knew who received which treatment. Fore! Foreign! Foreign! You guyschee. These are the results of the clinical trial. They show by how many points the normal RNA increased. A clear effect was observed in many patients who were given ariththramy. Significant improvements were also seen in other indicators. So this research truly shines as a ray of hope for patients who had given up on ever finding a cure. Yes. But before this drug can be used for patients, its safety and effectiveness have to be proven in a confirmatory trial and running clinical trials is very expensive. So we need to secure research findings. Approximately how long will it take to deliver ariththm to patients in need? We are aiming to make it happen within 3 years. Wow. within 3 years. That’s no time then. Yes. Yes. It’s definitely a step forward, but we don’t think it’s perfect yet. Uh we are working to make the treatment even better. Professor Nakamuri visits temples and historical sites whenever he can find a time. This is the five-storyried pagod of the Rudi Koji Temple, a national treasure located about an hour’s drive from the university. The roof of the pagoda is built by using a Japanese traditional technology uh called by Hadabuki and the eaves of aoda carving upward and the upper levels getting narrower. So its building, its pagoda looks slender and elegant. Uh visiting temples or shrines uh really makes me calm down. Uh I sometimes come up with uh ideas that move my research forward. This is the main hall of this temple. Uhhuh. And this is rice puddle. And that is uh pesu. These objects uh symbolize the Buddha’s deep compassion. He grinds his own body with that pesu and offers it to others with this rice paddle to save them. In a way, it it kind of relates to what you do as a job as well. So yes, also help others. Now you mentioned earlier that the treatment is not perfect yet and there are still things to do. What do you mean by that? So elroycing can definitely be expected to help treat my drophy patients but it’s not perfect. Uh for example uh if you lock your fingers like this your hands won’t come apart. Mhm. However, uh if you just wrap one hand around the other, uh they will come apart very easily. So there is some I think bind to the abnormal RNA uh relatively weak weakly something kind of that uh we try to find more uh selective binding partner with the abnormal RNA uh that won’t be come apart easily from the target. Uh for example what are they? Oh. Uh, actually it’s a protein that plants naturally have. A protein from plants. Yes. Oh, wow. This is theorocress, a plant widely found across the Eurasian continent. Its leaves are known to contain more than 400 types of proteins called PPR. PPR proteins play an essential role in processes such as photosynthesis. They bind strongly to RNA and regulate its activity. A research group at Kyushu University uncovered how the amino acid sequences that make up PPR proteins determine which basis of RNA they bind to. One of the essential members, Yusuke Yagi, is now working at a startup applying this knowledge to develop new uses for PPR. Yagi and his colleagues created multiple varieties of theocorocus in which the function of certain PPR proteins is switched off. Then they ground up the plants to extract the RNA. [Music] They investigated the relationship between PPR proteins and RNA almost as if they were cracking a secret code. This is how they were able to uncover the structure of PPR proteins that bind to each RNA base. They also succeeded in creating PPR genes with the exact sequence they wanted. [Music] [Music] [Music] This technology caught the attention of Professor Nakamoi at Yamaguchi University. [Music] If PPR proteins can bind strongly to each base of the RNA that causes myotonic distrophe, he thought that they might be able to block the activity of the abnormal RNA. [Music] Professor Nakamorei asked Yagi and his team to create PPR gene that binds to the CUG sequence of RNA. It was then administered to the mice with myotonic distrophe. [Music] These are the results. The mice treated with PPR showed a significant increase in the percentage of normal RNA. Using technology discovered and developed in Japan, you’re curing diseases at their root. This is groundbreaking achievement. Uh now that the technology is established, uh we can finally uh control the RNA that causes the illness. And will research on resin and PPR proteins continue in parallel? Oh yes, the PPR isn’t that simple. So it’s still in the animal uh study stage. We aim to uh treat mic droy patient as much as we can within while waiting for PPR uh to be ready for practical use. Uh what’s exciting about the PPR uh is that we can uh design them to bind to any RNA target. uh we hope we we aim uh so there are still many uh incurable diseases uh including neurological disease such as ALS that mediates abnormal RNA. I hope uh the PPR technology can help cure uh as many of these diseases as uh possible. I’m going to devote my life uh to put an end on the suffering of patients. Sato Mino continues training with how a robot suit that detects brain signals and assists with body movement. While the disease cannot be stopped, it’s believed that the robot suit can help slow the decline in her ability to walk. [Music] Sato continues her training, placing her hopes in Professor Nakamorei’s research. for [Music] [Music] [Music]
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Meet a Japanese neurologist working towards a cure for myotonic dystrophy, a rare disorder that progressively weakens patients.