1. Background Introduction

Parkinson's Disease (PD) is a common neurodegenerative disorder that mostly affects middle - aged and elderly people. Its etiology remains unclear and may be related to genetics, environmental factors, and the aging of the nervous system. The main pathological change is the degeneration and necrosis of dopaminergic neurons in the substantia nigra. Clinically, it is mainly manifested as resting tremor, bradykinesia, reduced facial expressions, increased muscle tone in the limbs, unsteady gait, balance disorders, sensory disturbances, insomnia, constipation, anxiety, and depression.

Parkinson's disease is a chronic progressive disorder that affects the central nervous system, leading to motor dysfunctions and other non - motor - related symptoms. Some of its behavioral symptoms are caused by the massive degeneration of dopaminergic neurons in the substantia nigra of the mid - brain. Dopamine is a neurotransmitter in our brain that controls movement. Factors such as genetic inheritance, environmental factors, and aging are all major risk factors. It mostly occurs in the elderly over 60 years old.

Currently, the average age of onset of Parkinson's disease in China is 60 years old, and the number of patients has exceeded 3 million. Parkinson's disease has become a common disease among middle - aged and elderly people, second only to tumors and cardiovascular and cerebrovascular diseases. In the early stage, patients may experience symptoms such as limb tremors, constipation, and indigestion, mainly manifested as depression and anxiety. In the advanced stage, patients may develop complications such as loss of self - care ability and pulmonary infection. In severe cases, pulmonary embolism may even occur. Movement imbalance disorders can cause fractures and other complications in patients. Some advanced - stage patients need to use urinary catheters and gastric tubes, which seriously affects their quality of life. With the intensification of population aging in China, the number of Parkinson's disease patients is increasing year by year.

It is estimated that by 2030, the number of patients will reach nearly 5 million, accounting for almost half of the global Parkinson's disease patients. Parkinson's disease is a chronic progressive disease, and every patient requires lifelong treatment and comprehensive management. Under the guidance of professional physicians, appropriate treatment plans should be adopted at different stages to better relieve symptoms and improve the quality of life.

2. Treatment Methods for Parkinson's Disease

2.1 Traditional Treatments

Currently, the mainstream intervention methods for Parkinson's disease mainly include drug intervention and surgical intervention. In the early stage of the disease, dopaminergic drugs can significantly relieve symptoms, and this stage is known as the "honeymoon period" of intervention. However, as the disease progresses to the advanced stage, due to the non - physiological dopamine concentration fluctuations in the body caused by drugs and their non - specific effects, the efficacy of such drugs gradually weakens. They are likely to induce adverse reactions such as dyskinesia and joint stiffness, and patients are often dependent on them, with most needing to take the drugs for life.

Surgical methods mainly include neurotomy and deep brain stimulation (DBS). Surgery can significantly improve motor symptoms, especially for limb tremors and muscle stiffness, but it has no obvious effect on somatic axial symptoms such as postural gait disorders. Moreover, surgery cannot cure the disease, so patients still need to continue drug treatment after surgery.

2.2 Stem Cell Therapy

As an emerging treatment strategy, stem cell therapy has brought new hope for the treatment of Parkinson's disease. Currently, the effectiveness of stem cell therapy for Parkinson's disease remains uncertain, and it is still in the clinical research stage. Some patients have shown positive effects after stem cell treatment, while others have not achieved significant results. Currently, several stem - cell - based treatment methods that are widely studied and have great potential mainly include the following:

Embryonic Stem Cells

Embryonic stem cells are totipotent and can differentiate into various cell types in the human body. In the research on the treatment of Parkinson's disease, embryonic stem cells can be induced to differentiate into dopaminergic neurons under specific in - vitro conditions. Then, through surgical transplantation, these differentiated neurons are implanted into the striatum of the patient's brain. For example, in some early animal experiments, dopaminergic neurons differentiated from embryonic stem cells were successfully transplanted into the brains of Parkinson's disease model animals. It was found that this could improve the abnormal motor behavior of the animals. The tremors, rigidity, and other symptoms of some animals were alleviated. Moreover, the survival of the transplanted neurons could be detected in the brain, and they established certain connections with the surrounding neurons and secreted dopamine neurotransmitters, thus supplementing the functions of the missing dopaminergic neurons.

Induced Pluripotent Stem Cells

Through gene reprogramming technology, mature somatic cells (such as skin cells and blood cells) can be induced and transformed into induced pluripotent stem cells (iPSCs) with characteristics similar to those of embryonic stem cells. These cells can also be induced to differentiate into dopaminergic neurons in vitro for transplantation treatment.

Neural Stem Cells

Neural stem cells exist in specific parts of the human nervous system and have the ability to self - renew and differentiate into various nerve cells such as neurons and glial cells. In the treatment of Parkinson's disease, neural stem cells can be obtained from fetal brain tissue or regions rich in neural stem cells in the adult brain (such as the dentate gyrus of the hippocampus). After in - vitro expansion and culture, they are transplanted into the patient's brain. Some studies have shown that transplanted neural stem cells can migrate and differentiate into dopaminergic neurons in the brain, supplementing the damaged neuron population and thus improving the patient's motor function.

Mesenchymal Stem Cells

Mesenchymal stem cells are widely sourced and exist in the interstitium of various human tissues and organs, such as bone marrow, adipose tissue, and umbilical cord. These stem cells have characteristics such as multi - directional differentiation potential, immunomodulatory function, and paracrine effects. In the research on the treatment of Parkinson's disease, mesenchymal stem cells do not directly differentiate into dopaminergic neurons to supplement the deficiency. Instead, they secrete a variety of neurotrophic factors and cytokines to promote the proliferation and differentiation of the original neural stem cells in the brain, protect the damaged dopaminergic neurons, inhibit the neuroinflammatory response, and regulate the local micro - environment, thereby alleviating the symptoms of Parkinson's disease.

3. Research Cases of Stem Cell Therapy for Parkinson's Disease

In recent years, with the development of regenerative medicine, stem cell therapy for Parkinson's disease has shown significant potential and promise. Based on existing research and clinical trial results, let's take a look at the safety and effectiveness of stem cell therapy for Parkinson's disease.

Case 1

On June 14, 2018, Academician Zhou Qi and his team from the Chinese Academy of Sciences published the article "Human Clinical - Grade Parthenogenetic ESC - Derived Dopaminergic Neurons Recover Locomotive Defects of Nonhuman Primate Models of Parkinson's Disease" in the journal *Stem Cell Reports*. The team tested the safety and effectiveness of neural cells derived from human embryonic stem cells in the treatment of Parkinson's disease in non - human primate models, providing pre - clinical data support for China's first Phase I/II clinical study on the treatment of Parkinson's disease based on embryonic stem cells (ClinicalTrials.gov number NCT03119636).

They differentiated mid - brain dopaminergic nerve cells from clinical - grade human embryonic stem cells. After strict quality inspection, these cells were transplanted into the brains of Parkinson's disease monkeys, and a two - year follow - up observation was carried out. The results showed that the implanted cells could survive and further mature in the animals for a long time, effectively improving the symptoms of Parkinson's monkeys. Moreover, no tumors or other serious adverse reactions occurred.

Case 2

On May 13, 2020, the Neurosurgery Department of Massachusetts General Hospital published the research results of "Personalized iPSC - Derived Dopamine Progenitor Cells for Parkinson's Disease" in the international journal *New England Journal of Medicine*.

Safety Assessment: 24 months after the first implantation and 18 months after the second implantation, the patient reported no adverse events or functional decline. **Conclusion**: Clinical and imaging results showed that the clinical indicators of Parkinson's disease symptoms tended to stabilize or improve 18 - 24 months after implantation.

Case 3

On May 9, 2024, Peking Union Medical College published the research results of "Phase 1 study of safety and preliminary efficacy of intranasal transplantation of human neural stem cells (ANGE - Soo3) in Parkinson's disease" in the international journal *Journal of Neurosurgery and Psychiatry*.

Safety Assessment:7 patients experienced a total of 14 adverse events during the 12 - month follow - up after treatment. There were no serious adverse events related to ANGE - S003. Safety testing revealed no safety concerns. Brain MRI showed no mass formation. **Conclusion**: Treatment with ANGE - S003 is feasible, generally safe, and well - tolerated, and is associated with functional improvement in clinical outcomes, with peak efficacy achieved at month 6.

Case 4

On November 29, 2020, the industry journal *Surg Neurol Int* published a research article titled "Mesenchymal stem cells in Parkinson’s disease: Motor and nonmotor symptoms in the early posttransplant period". Autologous mesenchymal stem cells (MSCs) were used to treat 12 Parkinson's disease patients. The MSCs were transplanted through intravenous injection or a combination of intravenous and intranasal injection.

Motor and non - motor symptoms and the overall quality of life were evaluated before transplantation and 1 and 3 months after transplantation. The results showed that the severity of motor and non - motor symptoms in the patients decreased significantly after the transplantation of mesenchymal stem cells.

In summary, stem cell therapy shows great potential in the treatment of Parkinson's disease, especially in relieving symptoms and improving the quality of life. Although most stem cell transplants are currently safe, their effectiveness varies. With the in - depth research and technological progress, stem cell therapy is expected to become one of the alternative treatment strategies for Parkinson's disease.

4. Summary of Research Registrations and IND Applications Related to Stem Cell Therapy for Parkinson's Disease

4.1 Clinical Research Registration Projects for Stem Cell Therapy of Parkinson's Disease

In January 2024, the "Clinical Research on the Treatment of Moderate to Severe Parkinson's Disease with Clinical - Grade iPSC - Derived Dopaminergic Neural Progenitor Cells" project jointly carried out by Shize Biomedical (Suzhou/Shanghai) Co., Ltd. and Shanghai East Hospital (Tongji University Affiliated East Hospital) was officially approved by the National Health Commission and the National Medical Products Administration (referred to as the "Two Committees") after multiple rounds of review by the National Stem Cell Clinical Research Expert Committee to conduct a national - level stem cell - registered clinical study (Approval number for clinical registration by the Two Committees and the Bureau: MR - 31 - 24 - 001927).

This project is the first clinical study on the treatment of Parkinson's disease with iPS - derived cells approved by the Two Committees and the Bureau in China. So far, the longest follow - up period of Shize Bio's clinical - grade iPSC - derived cell treatment for moderate to severe Parkinson's disease has exceeded 9 months. So far, there have been no adverse events related to cell therapy, and significant improvement trends have been observed in key efficacy indicators such as the "on - off" time and MDS - UPDRS score scale of multiple patients, as well as many non - motor indicators.

4.2 IND Applications and Approved Projects for Stem Cell Therapy of Parkinson's Disease

We can see that in the "Clinical Research Registration" (6 projects) and "IND Applications" (5 accepted, 4 approved) projects, the projects related to stem cell treatment of Parkinson's disease are not numerous. The types of stem cells involved include neural progenitor cells differentiated from embryonic stem cells, human neural stem cells, dopaminergic neural progenitor cells induced from neural stem cells, amniotic epithelial stem cells, and iPSC - derived dopaminergic neural progenitor cells.

It is worth mentioning that the "Human - Derived Dopaminergic Neural Progenitor Cell Injection" (NouvNeu001, Acceptance number: CXSL2300346), a globally first - in - class, chemically - induced, universal cell therapy product for Parkinson's disease, was completely independently developed by Ruijian Medical Technology Co., Ltd. (referred to as Ruijian Medicine). It has currently successfully completed the Phase I clinical trial. The data shows that it has good safety and tolerability and has successfully achieved the main research objectives. Moreover, the efficacy data of its secondary indicators has demonstrated significant market advantages. NouvNeu001 has also become the world's first iPSC - derived universal cell therapy product for Parkinson's disease to enter Phase II clinical trials.

On December 11, 2023, the National Medical Products Administration (NMPA) officially approved the IND application of Ruijian Medicine's research pipeline NouvNeu003 (Acceptance number: CXSL2300628) for early - onset Parkinson's disease, which became the second IND approved by Ruijian Medicine. This pipeline is aimed at Parkinson's disease patients with an onset age of less than 50 years old. Together with NouvNeu001, they form a strategic layout that targets the "early - onset" and "elderly - onset" Parkinson's disease patient groups, covering the entire life cycle and treatment cycle of both genetic and non - genetic types.

On February 22, 2025, the IND application of UX - DA001 Injection, an autologous iPSC (induced pluripotent stem cell) - derived cell drug for Parkinson's disease developed by Yuesai Biotech, was officially approved by the US Food and Drug Administration (FDA), making it the world's first iPSC - sourced autologous cell therapy drug for Parkinson's disease to be approved for clinical trials in both China and the United States. Yuesai Biotech achieved the "dual - filing and dual - approval" of its Parkinson's disease pipeline in China and the United States within 2 months.

5. Challenges and Prospects of Stem Cell Therapy for Parkinson's Disease

5.1 Challenges

Cell Source and Characteristic Issues

(1) Ethical Dilemmas: Embryonic stem cells have strong differentiation potential, but obtaining them often involves the destruction of embryos, which is restricted at the moral and ethical levels and has caused widespread controversy.

(2) Immunological Rejection and Tumorigenesis Risk: Both embryonic stem cells and induced pluripotent stem cells may face immunological rejection during allogeneic transplantation. Moreover, induced pluripotent stem cells may undergo gene mutations during the induction process, increasing the risk of tumor formation in the body.

(3) Differentiation Efficiency and Purity: Inducing stem cells to differentiate into specific dopaminergic neurons is crucial, but current technologies make it difficult to ensure the efficient and high - purity acquisition of the desired neuron types.

Transplantation Technology and Efficacy Maintenance

(1) Difficulty of Surgical Operation: Accurately transplanting stem cells into the striatum of Parkinson's disease patients' brains is extremely challenging. Brain surgery requires a high degree of precision, and even a slight deviation may cause serious nerve damage.

(2) Cell Survival and Functional Integration: Transplanted stem cells need to survive in the harsh micro - environment of the brain and establish effective connections with surrounding neurons to function. Currently, the cell survival rate is low, and the integration effect with host neurons is not ideal.

Clinical Evaluation and Regulatory Barriers

(1) Long - term Efficacy Monitoring: Parkinson's disease is a chronic progressive disease, and the long - term efficacy evaluation of stem cell therapy is of great importance. However, most current studies focus on short - term effects, lacking long - term follow - up data on the disease progression of patients several years later.

(2) Safety Assessment and Clinical Trial Standards: Ensuring the safety of stem cell therapy is a prerequisite for clinical application. Due to the lack of unified clinical trial standards and norms, it is difficult to accurately evaluate and compare the safety and effectiveness of different studies.

5.2 Prospects

Technological Innovation and Breakthroughs

(1) Optimizing Induction Differentiation Protocols: By deeply studying the molecular mechanisms of cell differentiation, new induction differentiation methods can be developed to improve the efficiency and purity of stem cell differentiation into dopaminergic neurons. For example, gene - editing technology can be used to precisely regulate the expression of key genes during the cell differentiation process, reducing abnormal differentiation.

(2) Improving Transplantation Technology and Micro - environment: Advanced cell transplantation technologies, such as using nanotechnology to assist cell delivery, can be developed to improve the transplantation accuracy. At the same time, by developing new biomaterials and drugs, the brain micro - environment can be improved to promote the survival and functional integration of transplanted cells. For example, designing biomaterial scaffolds with neuroprotective and trophic support functions can provide a suitable growth environment for transplanted cells.

Clinical Application and Development

(1) Personalized Treatment Strategies: With a deeper understanding of the pathogenesis of Parkinson's disease and individual differences among patients, personalized stem cell treatment plans based on patients' individual genetic and disease characteristics are expected to be realized in the future. By analyzing patients' genetic information and disease status, the most suitable stem cell type and transplantation method can be selected to improve the treatment effect.

(2) Combined Treatment Models: The combined application of stem cell therapy with other treatment methods will be the future development direction. For example, combining stem cell transplantation with drug treatment, physical rehabilitation therapy, gene therapy, etc., can comprehensively intervene in Parkinson's disease from multiple perspectives, enhance the treatment effect, and delay the disease progression.

Although stem cell therapy for Parkinson's disease faces many challenges, with the continuous progress of science and technology and in - depth research, it is expected to bring more effective treatment options and hopes of cure for Parkinson's disease patients in the future.