[Interview] Jinhyeob Ryu, CEO of Biorchestra

Alzheimer’s is one of the most devastating diseases known to mankind as, unlike most diseases, which inflict physical pain, it steals people’s precious memories one by one, aggravating the mental distress suffered by patients. Various types of research have been pursued in searching for treatments for Alzheimer’s, but so far all of these attempts have hit snags at critical moments and failed to make a breakthrough in discovering effective treatments. 

While even large-scale global pharmaceutical companies have been reluctant to come forward and tackle the disease, a biotech firm in Daejeon, South Korea has thrown its hat into the ring, garnering considerable international attention. As demonstrated by their name, "Biorchestra," the company is pursuing research to conquer Alzheimer’s by working in harmonious coordination like the members of an orchestra, under the direction of CEO Jinhyeob Ryu.

◆ RNA, a choice for fundamental treatment

CEO Jinhyeob Ryu found the fastest way to help Alzheimer's patients and their families, leading to the start-up of Biorchestra. <Picture=HelloDD>
CEO Jinhyeob Ryu found the fastest way to help Alzheimer's patients and their families, leading to the start-up of Biorchestra. <Picture=HelloDD>
A trend in new medicines has moved from in vitro to in vivo. Unlike an antibody that works against an antigen in the extracellular environment, this technique involves treating the problem inside the cell in a more fundamental way. With regard to this type of treatment, biomaterials are broadly divided into three groups: DNAs, RNAs and proteins. Biorchestra has focused its research for Alzheimers treatment in the RNA area. 

There are two main obstacles to the effective utilization of RNAs: short reaction time in the blood and the rate of penetration of the blood-brain barrier (BBB). Mr. Ryu explained, "Blood is a brutal environment for external substances like medicines, and, on top of that, normally RNAs are dissolved in around five minutes, making it difficult to count on effective treatment."

He went onto say, "A medicine also has to penetrate the blood-brain barrier in order to treat degenerative brain diseases like Alzheimer’s, but the average rate of penetration for elements such as antibodies are a mere 0.1% to 0.2%."

Biochestra has succeeded in extending the half-life (survival time) of RNA to 100 minutes, using an Oligonucleotide Transport Vehicle (OTV) technique, and has also enhanced the BBB penetration rate by coating the surface with small molecules more easily identified by receptors on the BBB. 

The company has also focused on a treatment that works within the brain once the BBB has been penetrated. Alzheimer’s produces abnormal β-amyloid and tau proteins, deteriorating patients’ memories. Attempts have been made by Biogen and Lilly to remove abnormal plaques (toxic proteins), using targeted antibodies, but so far, they have not been successful. 

The approach that Biochestra has chosen involves the use of "immune cells." CEO Ryu explained, "Our approach aims at activating patients’ immune cells, so that these cells can kill toxic proteins on their own. Since this approach, which aims at enhancing the patient’s innate immune system, is different from other treatments for Alzheimer’s, it has attracted a great deal of interest from the pharmaceutical industry."

Currently, Denali and Alector are also in the early stage of developing medical treatments utilizing immune cells; but there are some problems that must be addressed. The protein TREM2, found on the surface of immune cells, is a receptor that recognizes toxic proteins. A medicine administered to activate this receptor can invigorate phagocytosis, generating substances like IL-1β and TNFα. As inflammation factors, these two substances attack nerve cells and produce toxicity. In other words, the best treatment effects can be expected when a receptor called TREM2 is activated and, at the same time, the generation of immune-reaction factors is inhibited. Attracted by this approach, Biochestra has jumped on the bandwagon to develop a new medicine. 

CEO Ryu has analyzed the patterns shared by all degenerative brain diseases such as Alzheimer’s. He explains, "Symptoms of Alzheimer’s worsen as the accumulated toxic proteins weaken the function of the immune cells. We have focused on finding a treatment that does not diminish this function or can substitute for the function of immune cells."

The study of a treatment using microRNA from Biorchestra can overcome the shortcomings that existing Alzheimer's drugs had.
The study of a treatment using microRNA from Biorchestra can overcome the shortcomings that existing Alzheimer's drugs had.
The breakthrough that Biochestra has found is microRNA. It is effective in controlling the following two genes: CD** that performs phagocytosis just like TREM2 and S**** that inhibits inflammation. Because CD** and S**** become more robust the more microDNA is removed, they are able to instigate active phagocytosis and inhibit inflammation. 

Ryu also explained "Experiments on rats showed that toxic proteins disappeared and there was no inflammatory reaction. The key to our treatment lies in controlling two genes with OTV, a technology to penetrate the BBB, and RNAi that breaks down a single microRNA. Currently, we are in the stage of acquiring patents for these processes in major countries like the U.S."

Biorchestra’s ideas do not end here. They can be also applied to other degenerative brain diseases that share the same pattern as Alzheimer’s. Mr. Ryu specified, "The development of degenerative brain diseases like Lou Gehrig's, Parkinson's and Huntington's may all be linked to the accumulation of toxic proteins, Experiment on lab rats with Lou Gehrig's showed that the same treatment used for Alzheimer’s also enabled the rats to move their stiffened hind legs."

◆ Difficulties in gathering up performers ··· Now is the time to play together.

"The most difficult job was to muster up the people who could provide the necessary help. it took six months to find the right personnel and a full year to implement our pre-clinical strategy." 

After obtaining his Ph.D. in Pathology, Microbiology and Immunology at the School of Medicine at Tokyo University, Ryu chose to form his own firm. "I contemplated what would be the fastest way to treat an Alzheimer’s patient if the patient came to me," he said, and "There are many paths to choose from, including a university, a company or a research institute, but it is my belief that a start-up would be the fastest way and, thus, I decided to start my own business."

Like the mission of Biorchestra, the goal is to conquer Alzheimer's through collaboration between internal employees and business partners.<Picture=Biorchestra>
Like the mission of Biorchestra, the goal is to conquer Alzheimer's through collaboration between internal employees and business partners.<Picture=Biorchestra>
After first forming a start-up in Tokyo at the end of 2016, he moved to Seoul and embarked on his business in earnest starting from April 2017. The biggest difficulty he faced was finding suitable human resources. There was a shortage of highly-qualified research personnel and networks to turn to for advice. To help remedy this situation, the Bio Healthcare Association (BHA) has served as a bridge.  

He expressed his appreciation for their assistance, saying, "Through BHA, I was able to expand my network and keep up with the trends in the relevant fields," and that "BHA has now taken part in Series B, which has thankfully resulted in our procuring funding." 

Biorchestra’s Series B has been joined by Daily Partners, CKD Venture Capital, LSK Investment, NHN Investment, E&Venture Partners as well as BHA. Chung Kun Dang (CKD) Holdings, the holding company of Korea’s largest pharmaceutical firm (CKD), has made a strategic investment of 5 billion KRW, expanding the total investment to about 20 billion. 

Ryu further explained that "Our target is to reach the stage of out-licensing through steady technological complementation and verification," and "I have in mind to establish a foreign branch in Boston to facilitate this."

"Alzheimer’s is an indeed sad disease. Many pharmaceutical firms, research institutes and universities are working hard to find a cure for the disease. Biorchestra also plans to continue to play as a research orchestra that can bring new hope to many patients."

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