AI plus gene editing: how this company successfully treated adult thalassemia

VBDATA report | Since the completion of the Human Genome Project, we have been experiencing the rapid industrial development wave across three levels: reading genes, modifying genes, and in recent years, designing genomes from scratch. In fact, gene editing drug development is still in its early stage: indications all come from genetic diseases, clinical approvals are few and far between, and China has only one product IND. In recent years, as global regulators have continuously improved regulations and guidelines in a targeted manner, gene editing therapy has become an industry deeply participated in and highly anticipated by major international pharmaceutical companies, and the therapy is gradually expanding to high-incidence complex diseases and tumors. In May 2022, VB New Medicine interviewed Dr. Liang Junbin, Chairman and CEO of Reforgene, to discuss the current situation, pain points and breakthroughs of China's gene editing therapy field. Reforgene is a domestic gene editing drug company, one of the few in China with underlying CRISPR/Cas gene editing technology patents and development capabilities, and its team is also one of the earliest globally engaged in clinical translation of gene editing. Dr. Liang Junbin previously worked at the Guangdong Academy of Sciences and BGI, and is a serial entrepreneur in gene diagnostics and treatment, with more than 10 years of innovation and business management experience in molecular biology and genomics. The following is the interview transcript of Dr. Liang Junbin with VB New Medicine, edited without changing the original meaning for readers' convenience.

Globally in an early stage; domestic enterprises are expected to compete on the same stage with European and American peers

VB New Medicine: Please introduce your previous research and work experience. What technical and resource accumulation led you to found Reforgene?

Dr. Liang Junbin: My education, research and entrepreneurial experience have all been in the gene field, accumulating a deep technical and industrial understanding of human genetics and genomics. This understanding is a good accumulation and starting point for the development of gene editing medicines, so I chose to start a business.

Looking back over the past few years, gene editing technology has developed so rapidly. It has not only become popular as a core R&D tool, but has itself spawned a class of drugs. The advent of CRISPR gene editing technology first opened the door of hope for the treatment of genetic diseases, answering the question clinicians often raise: we have discovered the genetic problem, but how do we solve it?

Our co-founder Professor Huang Junjiu is also one of the earliest scholars exploring this path, applying gene editing technology to the treatment of thalassemia. Professor Huang Junjiu was also named one of Nature's "Top 10 Scientific Figures of the Year" in 2015. When the founders of Reforgene established the company in 2019, they were very clear about moving forward in the direction of gene editing medicines, and the first goal was to cure thalassemia.

VB New Medicine: Why did Reforgene choose gene editing therapy among the many sub-fields of medicine? What pain points and prospects did you see?

Dr. Liang Junbin: As mentioned above, this is a natural choice after we understood genes. There are still many human diseases that cannot be cured. I firmly believe gene editing will push drug development to a whole new level and bring good news to patients; this value cannot be replaced by other technologies. As an emerging field in its early development stage, most products of gene editing therapy are in the preclinical stage. Besides some common problems of drug development, there are more specific problems to solve, such as editing strategy and efficiency improvement, delivery specificity, control of off-target cutting or base editing point mutation off-target, on-target/off-target analysis and quality evaluation.

But in fact, precisely because gene editing therapy is in an early stage globally, it is one of the medical directions in which domestic enterprises can compete on the same stage with European and American peers. From the perspective of industrial application, domestic development is relatively fast, and indications are gradually expanding from rare diseases to broader diseases, including chronic degenerative diseases and malignant tumors.

CRISPR gene editing is an underlying technology of the life sciences, with many application fields, unlikely to become a red ocean

VB New Medicine: Looking back at industry development over the past few years, how has the understanding of domestic venture capital institutions toward CRISPR gene editing technology changed? How do you view the medical value of this technology?

Dr. Liang Junbin: This is an interesting question. I think gene sequencing, gene editing and synthetic biology can be regarded as the "three great mountains" of the entire life sciences, with far-reaching value in medicine. Among them, gene editing technology has curative and disruptive value, equivalent to performing surgery on humanity's "book of life". At the current stage, early companies like us play the role of trailblazers: from solving monogenic diseases causally related to genes, to complex diseases where gene mutations or loss of control act as some kind of "contributor", such as chronic diseases, hematologic tumors and solid tumors.

As for how far it can go? We do not know. But one thing is certain: the boundary will keep expanding. At present, the industrialization of gene editing is still at a relatively elementary stage, and everyone's overall understanding depends on the degree of mastery of gene editing tools and the depth of understanding of diseases. But being in an early stage of development does not mean its future application is narrow; gene editing is not a niche technology field. Its impact on all aspects of life science development is far-reaching, and it will form a large industrial landscape.

In 2018, when I first communicated with some investment institutions, most of them took a wait-and-see attitude and did not see the technology as particularly distinctive. But two major events influenced their attitude. One was the success of clinical treatment with thalassemia gene editing therapy; the other was the two pioneers of CRISPR gene editing technology jointly winning the 2020 Nobel Prize in Chemistry. These events brought confidence, promoted the development of the related industry and investment, and people began to show more interest in the industry, with recognition increasing. Some leading investment institutions explicitly stated that they would position the gene editing industry as an investment priority.

At present, Reforgene's thalassemia product has shown curative efficacy in some cases, and early R&D is being carried out simultaneously in several chronic disease areas in ophthalmology and the nervous system. On the other hand, we also see the trend of immune cell therapy moving from individualized to universal, in which gene editing technology plays a key role. It is worth mentioning that the diagnostic industry of CRISPR/Cas technology is also taking shape, with two overseas companies, Mammoth Biosciences and Sherlock Biosciences, currently positioned in this field. There is no doubt that gene editing, as an underlying technology of the life sciences, will bring revolutionary changes to human health.

VB New Medicine: CRISPR gene editing medicines have an imaginative development prospect. Will this industry quickly turn from a blue ocean into a red ocean?

Dr. Liang Junbin: Valuable industry directions will inevitably attract more entrants, but I don't think this field will quickly become a red ocean. First, gene editing is a technology that is easy to learn but difficult to master, and is unlikely to become fast-food entrepreneurship. Second, drug R&D has a long cycle and high investment intensity; not many enterprises can settle down, or have the ability to settle down. Making friends with time is difficult for many people. On the other hand, gene editing is an underlying technology widely applicable in disease treatment. There are about 8,000 rare diseases clearly defined by humans alone, and many non-hereditary diseases as well. There are many optional indication development directions, and enterprises will also develop their own unique technical routes, so it is unlikely to become a red ocean.

Completing China's first successful treatment of adult thalassemia, entering a hundred-billion-level market

VB New Medicine: Please talk about the clinical research progress of Reforgene's beta-thalassemia gene editing medicine.

Dr. Liang Junbin: This is Reforgene's first R&D product. Thalassemia is the monogenic genetic disease with the widest affected population worldwide. Gene editing medicines are currently considered internationally the best choice for a complete cure of thalassemia. CTX001, being developed by CRISPR Therapeutics of the United States for transfusion-dependent beta-thalassemia, has achieved excellent clinical trial progress and is widely regarded as a blockbuster drug about to be launched.

Reforgene has completed investigator-initiated thalassemia clinical research, and the data show significant efficacy: the subjects have been cured and discharged into follow-up, with key clinical indicators such as hemoglobin content and time to transfusion independence at industry-leading levels. This is also the world's first clinical study of a novel-target thalassemia gene editing therapy, and the first successful treatment of adult thalassemia patients in China. Our data will be announced at the upcoming 2022 European Hematology Association Congress (EHA), which is also the first clinical report of a domestic thalassemia gene medicine at the congress.

VB New Medicine: What other advantages and achievements does Reforgene have in gene editing medicines?

Dr. Liang Junbin: Reforgene uses innovative DNA editing and RNA editing as drug development strategies, and has laid out multiple directions beyond hematopoietic stem cells, including ophthalmic product development for retinitis pigmentosa and two blinding diseases, with some data reaching internationally advanced levels. In Parkinson's disease, Reforgene has successfully achieved neuronal regeneration through RNA editing, and positive preliminary efficacy results have been seen in monkey models. In addition, we have some good early data that will be gradually announced in the future.

VB New Medicine: How does Reforgene use AI to accelerate gene editing drug development? Why do this work?

Dr. Liang Junbin: We want to do real innovation and take the difficult but correct path. On one hand, due to the characteristics of gene editing itself, it is a highly programmable drug technology that can be understood as a digital drug form. On the other hand, gene editing changes the nucleic acid sequences of genetic material; to do this well requires mastery and application of genomics, and genomics is essentially data science. Reforgene has a technology innovation platform called TIPBAIG™ (Therapeutic Innovation Platform Based on Informatics and Genomics), aiming to combine Bio and IT capabilities to accelerate drug R&D efficiency and underlying innovation. We have built a dedicated AWS cloud platform, integrating machine learning, data mining and protein structure prediction technologies.

Technological innovation is not easy; it requires the mindset of "building a strong fortress and fighting a steady war". Starting from the unique combined background of the founding team in genomics, molecular and cellular biology and computer science, and combining independent R&D with strategic cooperation, Reforgene has achieved some innovative results in CRISPR editing tools. It is worth mentioning that Reforgene is one of the few enterprises in China with underlying CRISPR patent technology. Among them, our original CRISPR/Cas13m has efficient cleavage capability and low off-target levels, and its small size makes it easy to package. CRISPR/Cas13m technology can be widely applied to knockdown, modification and base editing at the RNA level, with higher targeting specificity than RNA interference technology and unique advantages in disease treatment.

VB New Medicine: Based on the above advantages and achievements, Reforgene completed three rounds of financing in just over two years, and last year gained recognition from institutions including YuanSheng Capital, BioTrack Capital, Hillhouse Venture and Sinovation Ventures. With the dual support of capital and technology, what are Reforgene's short-term goals and long-term plans?

Dr. Liang Junbin: Reforgene is committed to developing curative medicines for serious diseases. We have recently achieved milestone progress in hematology and ophthalmology products. Centered on gene editing, we will lay out pipelines in two fields, genetic diseases and major diseases, including products for the liver, neurology and tumors. These are our long-term plans. At the same time, we will adhere to the dual-engine strategy of products and technology, like the two engines of an aircraft, becoming the power source of the company's development. Reforgene aims to become an innovative drug company with original technologies and global competitiveness and influence. Reposted from: VBDATA http://www.vbdata.cn/55119