Source: Zhang Tongshe

Imagine this scenario:

When you are diagnosed with Parkinson's disease, the doctor tells you, "Don't worry, we will implant new nerve cells in your brain." then several cells will be extracted from your body and sent to the stem cell factory. A group of researchers reprogrammed and genetically edited the cells and cultured new nerve cells. Two to three weeks later, the doctor will perform surgery on you to implant these cells. Soon after, you are back to normal again, and the involuntary tremor of the body is finally gone.

This scene sounds like science fiction, but it is becoming a reality little by little. What underpins such ideas is a new treatment model of modern clinical medicine-regenerative medicine. Regenerative medicine, known as the "third medical revolution", takes stem cell technology as the underlying core technology, which has brought unprecedented breakthroughs to the medical community.

Japanese scientist Shinya Yamanaka's team first reported on iPSC (induced pluripotent stem cells) in the journal Cell in 2006 and won the Nobel Prize in Physiology or Medicine in 2012. Since then, it has opened an important branch of stem cell therapy.

In 2021, Ouyang ping, who has been involved in the biomedical industry for 12 years, founded Yuanwu Medicine, which is ready to further cultivate in the field of iPSC technology.

Long before the establishment of the company, Ouyangping had a clear reflection on the technical direction, technical key points and technical model. At present, Yuanvore Medicine is building three platforms around iPSC technology, including iPSC reprogramming process platform, iPSC directed differentiation technology platform and iPSC genetic engineering platform, and gradually improve the technical matrix.

"There is no so-called zero-sum game in the application market of iPSC technology, this is the sea of stars." Ouyang Ping said.

Ouyang ping, the founder of Yuanvore Medicine

Anchor the direction of regenerative medicine.

After several twists and turns, he decided to do stem cell drug research and development independently.

In 2012, Ouyang ping officially entered the biomedical industry, nearly 15 years after he first entered the society.

During the more than ten years from graduating from university in 1997 to joining the biomedical circle, he has been going back and forth between the north and the south, moving his job and city many times, and constantly adjusting the direction of his life. He has worked as an employee of a state-owned enterprise, a manager of a foreign enterprise, and a corporate partner, and has been involved in many fields, such as banking, fast consumer goods, retail, chain catering, integrated circuits and so on.

"when I was young, I was a person who was very difficult to follow the established track and was always adventurous." After various attempts and experiences, Ouyang ping made up his mind to enter the biomedical track based on the judgment of the country's development direction and industrial prospects.

The time came in April 2012, when Ouyang ping came to Shanghai to begin the new journey of his career.

After arriving in Shanghai, he first joined an integrated circuit company, responsible for the R & D and industrialization of strategic emerging projects. After the completion of the project, he coincided with the expansion of enrollment before the listing of Lanwei Medicine. By chance, he joined the medical company. Ouyangping, who was born as a liberal arts student, was responsible for handling the company's affairs in the president's office. "this is my first official entry into the biomedical industry, and it was Lanwei Medicine that brought me in."

During his three years of work in Lanwei Medicine, Ouyang ping's understanding of the biomedical industry has gradually matured, coupled with his sensitivity to the development of the industry, he has a premonition that his future will belong to this industry. In his words, "we must continue to move in the best direction in the industry."

In 2016, Ouyang ping joined Yisi Medicine, the first entrepreneurial team in his life, as a partner. During this start-up period, he went through almost every link of the entrepreneurial chain, including industry-university-research cooperation, clinical registration, brand marketing, sales cooperation projects and so on.

From patented technology to results transformation, from clinical trials to market access, from brand marketing to IPO declaration, Yisi Healthcare has given him one of the most valuable experiences in the biomedical industry.

Five years later, Ouyang ping, who reached a career bottleneck, chose to leave Yisi Medicine for the time being. "after I left, one of my thoughts was very certain that I wanted to lead a team to start a business on my own," he said. "

In the early days of starting a business, Ouyang ping was exposed to regenerative medicine. Regenerative medicine refers to the use of biological and engineering theories and methods to create missing or functionally damaged tissues and organs to make them have the structure and function of normal tissues and organs. "I was very excited at the time and it was an area that really needed innovation. The underlying core technology of regenerative medicine is stem cell-related technology, and choosing the direction of regenerative medicine means the research of stem cell-related treatments and drugs. "

In May 2021, Yuanvore Medicine was established, and Ouyang ping began to plan to set up a team and refine the specific technical direction.

After communicating with stem cell experts, he anchored the direction of iPSC technology. IPSC technology is to input a series of inducing factors into mature somatic cells and reprogram them into a kind of pluripotent stem cells with characteristics similar to embryonic stem cells. This kind of stem cell has more potential for development and application than other types of stem cells.

However, because there are very few talents in the field of iPSC technology in China, Ouyangping just wanted to use license in to get overseas technology license, and then establish a cooperative development relationship with foreign companies. But after an in-depth understanding, he found that this road would not work.

First, China has a strict negative list in gene editing and cell therapy, and domestic companies are unable to introduce foreign investment; second, western countries with developed biomedicine have also imposed a certain technological blockade on China in this field.

"If we can't introduce technical cooperation, we can only develop it ourselves."Ouyangping sighed. Looking back, I found that there are many powerful scientists in the field of stem cell technology in China. After repeated exchanges with domestic experts in related fields, he established a cooperative relationship with many of them and set up a technical team step by step. At the end of 2022, this cell therapy project based on iPSC technology was officially launched.

Although it is a start-up, Yuanvore Medicine has attracted elite talents from well-known universities at home and abroad, including doctors and postgraduates from Shanghai Jiaotong University and Chinese Academy of Sciences, as well as stem cell talents jointly cultivated by China and the United States. It is worth mentioning that the company also introduced the sister-in-law of Nobuya Yamanaka, a Nobel Prize winner who graduated from Kobe University. In addition to the formation of the internal team, the company also has a number of external cooperation institutions, including Tongji University, Shanghai University of Science and Technology and so on.

Although Ouyang Ping does not come from a technical background, the experience gained from the industry in the past has given him a unique entrepreneurial logic. "starting from the nature of clinical drugs, reversing the whole technical logic is the core of my business." The key, he stressed, is the integration of technology.

Build three major technology platforms.

Determined to overcome the difficult problem of allogeneic treatment

According to statistics, the global market of regenerative medicine will reach 50.44 billion US dollars in 2025, and the Chinese market will reach 46.88 billion yuan. As of May 2023, there have been 6463 clinical trials in the field of regenerative medicine stem cells worldwide, involving 200 indications, and 19 products have been approved to market.

However, in the field of cell therapy based on iPSC technology, no drug has been approved and put on the market all over the world.

Ouyang ping said: "the fast-moving domestic enterprises are in the clinical phase I, and now the iPSC technology-related therapy is in its infancy."

As an important branch of stem cell therapy, what are the characteristics and advantages of iPSC technology?

Dr. Jin Jun, general manager and CTO of Yuanwu Medicine, said: "the treatment concept of iPSC technology is to add. If you have some cell defects in your body, we first let iPSC differentiate into the cells you need in vitro, and then transplant them into the body, and restore the normal operation of the body by repairing and replacing damaged or dead cells."

The advantage of iPSC is that it is very similar to embryonic stem cells in morphology, gene and protein expression, epigenetic modification, cell doubling ability and differentiation ability, and can avoid the ethical problems caused by embryonic stem cells.

Although only a year after its establishment, Yuanwu Medicine has set up a complete underlying technical platform and pipeline system for different indications of degenerative diseases.

Based on iPSC technology, the products being studied by Yuanvore Medicine are mainly distributed in three areas: nervous system, immune system and metabolic system. "for example, Alzheimer's disease and Parkinson's disease, these two brain degenerative diseases are actually caused by cell defects in some nerves in the brain, but neurons are non-regenerative, so the use of traditional drugs is only to relieve symptoms, the effect is very limited. With its unique unlimited proliferation ability and developmental totipotency, iPSC is expected to 'solve' the difficult problem in the treatment of chronic degenerative diseases. "

Platform is the basis of product research and development. In the construction of technology platform, Yuanwu Medicine plans to build three platforms-iPSC technology reprogramming process platform, iPSC technology directed differentiation platform and iPSC technology genetic engineering platform.

Yuanvore Medicine Research and Development Center

Specifically, the reprogramming process platform will be used to develop an efficient and non-integrated iPSC gene reprogramming process to obtain seed cells of stable iPSC technology, and the directed differentiation platform will be used to explore the differentiation of stem cells in vivo and in vitro in the future. The genetic modification platform is used to genetically modify specific cells, "for example, we need to regulate some cells to secrete certain cytokines, thus increasing their tolerance to the pathological environment after they are transferred into the human body."

In terms of indications, Yuanwu medicine preferred Parkinson's disease and osteoarthritis. At present, the two pipelines are still in the stage of development.

Dr. Jin Jun said that iPSC technology is facing two major problems at the present stage: first, in the research and development stage, the efficiency of using iPSC technology to obtain specific cells is relatively low, and the time cost and economic cost are difficult to control; second, in the production stage, "how to prepare cells on a large scale" is a difficult problem that the whole industry is constantly overcoming. "it's easy to make a cell line in a laboratory petri dish, but if you want to make a cell drug, you have to produce it on a large scale, which is what Yuanvore Medicine will strive to achieve in the future."

In the treatment mode, Yuanvore medicine will slowly transition from autologous therapy to allogeneic therapy. "autotherapy is the main treatment in the early stage, and the drugs we develop in the future must be universal." Dr. Jin Jun said that researchers will try to knock out gene fragments related to immune rejection by gene editing to obtain general-purpose drugs.

Seize the rare window period.

"the sun is about to rise."

From the birth of the concept of cell therapy in the 1990s, to the invention of iPSC technology by Yamanaka's team in 2006, and now some biomedical companies at home and abroad have begun to try to use iPSC technology to develop drugs. In Ouyang Ping's view, this technology has developed to a rare window period.

"The foundation of iPSC technology is basically complete, and this technology will soon become a drug of clinical value, and people who really understand the integration of industry and technology are needed."

From the perspective of development opportunities, he believes that compared with foreign countries, the domestic market conditions are more mature. "the current political environment and market environment are relatively stable, the technology reserve is abundant, and the whole biomedical industry chain is very sound."

However, at present, there is a shortage of talents in the field of iPSC technology in China. "it is very difficult for us to recruit a talented person." Ouyang ping said that in order to solve the talent problem, Yuanwu Medical University and Shanghai University of Science and Technology have worked together to train postgraduates in the field of iPSC this year.

Referring to the future development plan, he said that in the technological path, the company currently focuses on Parkinson's and osteoarthritis, and will develop around the major pipelines of the neural, immune and metabolic systems in the future. it is expected that by the end of 2028, 4-5 products will enter phase I and II clinic, and 4-5 products will enter scientific research and clinical research. In terms of industrial development, the company hopes to empower innovation and accelerate the process of industrialization with the help of the capital market. In terms of capital preparation, the company is expected to complete the pre-A round of financing by the end of this year.

"Although iPSC-based cell therapy is still in its infancy, the dark period is almost over, and now it's like three or four o'clock in the morning, when the sun is about to rise." Ouyang Ping sighed.