Frost & Sullivan Exclusive Interview with Rui Zhen Regenerative Medicine — Stem cell therapy holds great promise for treating neurodegenerative diseases and cancer, with a broad market

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By establishing primate models to understand and study human brain diseases, we have made some good progress so far.

Let's take Parkinson's disease research as an example. Many major theories about Parkinson's disease originate from in vitro experiments. One type of Parkinson's disease is a typical genetic form called early-onset Parkinson's disease, which can be caused by mutations in two single genes (PINK1 and Parkin genes). The corresponding PINK1 protein is a serine/threonine kinase, while Parkin is an E3 ubiquitin ligase. Homozygous mutations in these two genes can lead to Parkinson's disease. Previous studies suggested that these two genes act on the same pathway. Many in vitro studies have confirmed that if mitochondria are damaged, PINK1 dephosphorylates PRAK, thereby clearing mitochondria and protecting nerve cells. This is the famous mitochondrial autophagy theory in the field. However, this hypothesis cannot be verified in mouse and Drosophila models because knocking out the corresponding genes does not cause death of the corresponding nerve cells in these two animal models.

However, as our research deepened, we found that knocking out these two genes could reproduce corresponding disease symptoms in non-human primate models. In monkey models, it was discovered that knocking out the PINK1 and Parkin genes could lead to neuronal cell death characteristics similar to those seen in human brains. Therefore, these genes may only play their corresponding roles in higher animals and are specific—meaning that they are expressed and function only in human brain tissue and cannot exert the same effects in mice and fruit flies. This proves that when studying human brain diseases, we need to use more human-like animal models to better represent the special pathological changes of the human brain.

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With the absolute increase in population and the intensification of global aging, the number of people affected by neurodegenerative diseases will continue to grow in the future. Fortunately, in recent years, with technological progress, we have made further advancements in the field of diagnosis and treatment of neurodegenerative diseases. Taking representative examples such as Alzheimer's disease and Parkinson's disease as examples.

With the deepening research on Alzheimer's disease, it has been found that there are two important characteristics: one is the presence of neurotoxic β-amyloid (αβ) deposits in the brain, and the second characteristic is the formation of neurofibrillary tangles (NFTs) in Tau proteinopathies. After confirming these two main pathological features, they are of great help in disease diagnosis. Currently, effective diagnosis can be made by combining brain imaging with the patient's symptoms. Furthermore, can we predict whether Alzheimer's disease will occur at an earlier stage? This involves research on biomarkers, which refer to biochemical indicators that can mark changes or potential changes in systems, organs, tissues, cells, and subcellular structures or functions, occurring before symptoms appear. Before the onset of symptoms in Alzheimer's disease, can we predict whether the disease will develop by observing biomarkers in blood or cerebrospinal fluid? Recently, the research team led by Professor Yu Jintai, in collaboration with Professor Feng Jianfeng's team, found that based on plasma proteomics data from large population cohorts and artificial intelligence algorithms, the risk of developing dementia diseases including Alzheimer's disease, new-onset all-cause dementia, and new-onset vascular dementia can be predicted using plasma protein GFAP, with a prediction time that can be advanced by 15 years. In the field of neurodegenerative disease diagnosis, it is believed that there will be new breakthroughs in the coming years.

In the treatment of neurodegenerative diseases, cell therapy has also made good progress. Immunotherapy for Alzheimer's disease has also made significant strides; by targeting antibodies against αβ amyloid deposits, it can alleviate cognitive decline in 35% of patients and reduce the risk of progression to the next stage by 39%.

The typical feature of Parkinson's disease is the death of dopaminergic neurons in the substantia nigra and striatum, leading to reduced dopamine release. Cell therapy, which aims to regenerate dopaminergic neurons in the substantia nigra and striatum, may effectively alleviate symptoms in patients. Currently, a stem cell therapy composed of dopaminergic neurons produced by pluripotent stem cells (Bemdaneprocel, BRT-DA01) has begun clinical trials. This stem cell therapy involves surgically implanting differentiated neuron cells into the brains of Parkinson's patients, potentially reshaping the neural network damaged by the disease, and is expected to restore motor and non-motor functions. The phase I clinical study has reached its primary endpoint, with good patient tolerance, and plans are underway for phase II clinical trials. Rui Zhen Regenerative Medicine also has many arrangements in this area for treating neurodegenerative diseases through stem cell therapy. Currently, several therapies are actively being explored.Among them, the Parkinson's disease pipeline iDA001, which is progressing at the fastest pace, has successfully completed the pharmacodynamic validation in primates and preliminary CMC exploration.

In the treatment of Huntington's disease, gene therapy has also made good progress. Last year we published inNature Biomedical EngineeringA study published in a journal has confirmed that by repairing mutant genes in large animal models of Huntington's disease using gene-editing technology and replacing them with normal genes, the neurological toxicity and symptoms of the pig model can be improved. This supports the further use of gene therapy for the treatment of genetic diseases in neurodegenerative disorders.

Stem cell therapy still faces many challenges in the treatment of neurodegenerative diseases.

The first problem is regeneration, which remains a controversial topic in current research. If cells in the human brain can regenerate, what are the regeneration rate and efficiency? If the regeneration rate is only 1%, can it be used for treatment? Additionally, how long does it take for regenerated cells to be generated in the brain during treatment?

The second aspect is immunogenicity; foreign cells are rejected by the body's own cells, triggering an immune response to eliminate them. As a result, the transplanted stem cells cannot exert the therapeutic effects they were intended to. Currently, attempts are being made to use iPSC cells for regeneration and reduce immunogenicity for treatment;

The third is stem cell tumorigenicity.Although the oncogenic risk can be controlled within a very low range with the help of current product design and CMC quality inspection processes, long-term safety still requires more clinical samples and longer time for verification.;

Finally, there is the issue of drug efficacy, which refers to how stem cell drugs are delivered to the treatment site. There have been some studies on delivery methods, but these methods still need further exploration in the treatment of brain diseases. Fortunately, many patients currently have a high acceptance rate for stem cell therapy, which will further promote the clinical progress of stem cell therapy.

The purpose of engaging in basic research is to advance related fields and ultimately apply the findings to clinical practice, helping patients with neurodegenerative diseases receive treatment. Our team has previously been mainly engaged in basic research, and joining Rui Zhen Regenerative Medicine is also an opportunity for us to establish non-human primate models that can better promote translational research and achieve strong collaborations.

Rui Zhen Regenerative Medicine has currently established a comprehensive range of technologies including iPSC reprogramming and cell bank, immune and neural cell differentiation preparation techniques, as well as gene modification to construct engineered iPS cell lines, covering the entire process of iPSC cell therapy. The dopamine precursor cell differentiation preparation technology independently developed by Rui Zhen Regenerative Medicine has been authorized and is the first domestic enterprise to obtain relevant patent authorization. This product has completed pharmacodynamic verification studies in a primate Parkinson's disease model with ideal therapeutic effects, and an IIT clinical research project cooperation is currently underway. In addition, Rui Zhen focuses on the preparation of high-purity iNK derived from iPSC and the development of multi-module NK-enhanced iPSC products. It has established a high-purity differentiation technology for iNK and completed the first domestic animal experiment on engineered iNK. ADCC-enhanced iNK has shown strong tumor clearance and recurrence inhibition effects, which will provide a new treatment direction for tumor therapy.

Therefore,If basic research in universities and research institutes can collaborate effectively with Rui Zhen's reliable translational experience in regenerative medicine,There is hope for a complete chain from basic research to clinical translation, thereby promoting the launch of more drugs for the treatment of neurodegenerative diseases and cancer.

In the field of neurodegenerative diseases, Rui Zhen Regenerative Medicine holds the only authorized patent in China for the differentiation and preparation of dopamine cells highly relevant to Parkinson's disease treatment. In the field of immune cell therapy, Rui Zhen Regenerative Medicine has established patents for iPSC-NK cell differentiation and various gene-edited enhanced iPSCs, covering two key directions: cell differentiation and preparation, as well as functional enhancement in tumor immune cell therapy. It has become the first company in China to publish experimental results demonstrating strong tumor-killing effects of engineered NK cells derived from iPSCs in animal models.

Currently, Rui Zhen Regenerative Medicine has multiple clinical pipelines in progress, including two lines targeting neurodegenerative and oncology treatments: iDA001 and iNK001. It is also advancing product pipelines for Huntington's disease, stroke, and amyotrophic lateral sclerosis (ALS), which are currently in the reserve pipeline planning phase.

Currently, globally, many companies and research institutions are dedicated to the development of iPSC cell therapy. There are mainly two key aspects: First, the quality and performance of iPSC cells prepared in different regions vary, depending on the experience and research capabilities of companies and research institutions. Rui Zhen Regenerative Medicine has very rich experience in cell culture, regeneration, and gene editing to differentiate iPSC cells into the desired cells; secondly, it is the therapeutic effect of iPSC cells, that is, whether iPSC cells can achieve the result of treating neuronal cell death in the brain. Currently, many studies use mouse models, which do not exhibit the characteristic of neuronal cell death, making it difficult to evaluate therapeutic effects. Rui Zhen Regenerative Medicine combines non-human primate models to effectively assess treatment outcomes, and then combines this with its previous rich experience to achieve a better clinical treatment result from in vitro to in vivo, through large model verification, and finally to achieve good clinical outcomes in clinical practice, further promoting the company's development.

In the future, on one hand, we will establish more, more precise, and more useful non-human primate models. A problem currently faced by these large animal models is that they have a relatively long breeding cycle; mice have a reproductive cycle of over twenty days, while monkeys can reach over one hundred sixty days. This is a challenge that limits the company's research and development efforts. We are currently experimenting with gene editing at specific brain regions in adult large animal models to create very typical characteristics of neuronal cell death, which will help us with our research on neurons. We can observe whether local stem cell therapy in the brain can restore dead cells and thus assess the therapeutic effect. By further integrating animal models with stem cell therapy, we aim to explore more diverse and suitable new research paths.