When a nerve is damaged, it is difficult to recover. There are drugs that alleviate the symptoms of degenerative cranial nervous system diseases caused by nerve damage, but drugs that control the disease are rare. Therefore, development of regenerative treatment using stem cells to replace damaged nerves is being made for Parkinson’s disease. No drug has been developed yet, and many clinical trials are in progress.
Parkinson’s disease is a neurological disease suitable for application of stem cell therapy. This is because nerve damage is limited to a specific area of the brain, and it is expected that symptoms will improve if only this area is treated intensively. Although Parkinson’s disease varies in the type and severity of symptoms from patient to patient, motor symptoms are common. Motor symptoms are due to damage to the dopaminergic neurons of the motor circuit. By the time a patient is diagnosed with Parkinson’s disease, more than 50% of dopaminergic neurons have been damaged. So, it is a treatment to improve symptoms by supplementing dopaminergic nerves by transplanting cells.
In Parkinson’s disease, in addition to showing motor symptoms due to damage to the dopamine nerve, non-motor symptoms are also shown due to damage to the autonomic nerve. Clinical trials for current cell transplantation treatment are mainly conducted for the purpose of improving motor symptoms by supplementing dopaminergic nerves, and it is difficult to expect an improvement effect on non-motor symptoms in which dopamine nerves are not involved. Since the symptoms of Parkinson’s disease appear in various ways for each patient, clinical trials are conducted by selecting patients whose motor symptoms are the main problem.
The dopaminergic nerve that composes the motor circuit in the brain is located in the most central part of the brain called ‘substantia nigra’. In Parkinson’s disease clinical trials, cells are transplanted to the striatum where the terminals of dopaminergic neurons reach. When dopamine cells are transplanted into the substantia nigra, the transplanted cells must settle down, interact with other cells around them, branch out, and differentiate so that the terminal part of the cell reaches the striatum. The environment and conditions for differentiation are complex and take too long. need.
If a patient has to wait for several years for the effect to appear even following undergoing brain surgery, it will not help the patient with severe symptoms right away. So, in reality, dopamine cells are injected directly into the striatum, which is the nerve terminal, to settle and survive, thereby restoring the dopamine-secreting function. In other words, cell transplantation does not restore motor circuits. However, the effect of symptom relief is expected through cell transplantation.
Currently, the treatment of Parkinson’s disease is mainly aimed at relieving symptoms by administering levodopa. Levodopa is a very effective drug, but with long-term administration, patients gradually develop dyskinesia or catatonia. The dopaminergic nerve not only functions to produce and secrete dopamine, but also is a place to continuously release dopamine following converting levodopa into dopamine and storing it.
As Parkinson’s disease progresses and dopamine nerves are reduced, the storage capacity of dopamine is also depleted and dopamine supply becomes unstable, so even if levodopa is administered, the patient shows dyskinesia. In this case, the current available method for the patient is to use other dopamine-acting drugs instead of levodopa or to perform deep brain stimulation. By locally restoring the dopamine neurons in these patients and allowing them to secrete dopamine in a controlled manner, the patient’s quality of life is greatly improved.
Transplantation of cells does not remove the cause of Parkinson’s disease in the patient. As a biomarker for Parkinson’s disease, aggregation of a protein called synuclein appears in areas of the brain where the disease has progressed. When the brain of a patient who died following living for a long time following cell transplantation was autopsied, there is a case in which synuclein was spread even in the transplanted part. In other words, Parkinson’s disease continues to progress despite cell transplants, but by replenishing dopamine cells through cell transplants, patients can buy time before serious symptoms appear.
Early clinical trials were carried out by transplanting primitive nervous system tissue or cells from embryos six to eight weeks following conception into Parkinson’s disease patients. Movement symptoms improved in some of the transplanted patients, and the effect was sustained. Early clinical trials have led to technological advances in regenerative therapy. In addition, it became possible to review side effects and inherent problems. For example, dyskinesia may appear following transplantation, but it is believed that it can be improved technically. Transplanted cells should settle, differentiate, survive for a long time, but not divide. This is because transplanted cells can divide and proliferate to form tumors.
Even now, clinical trials are under way to transplant embryos to patients with Parkinson’s disease in a program called ‘Trans Euro’, which is jointly conducted by several universities in the European Union. However, transplanting part of an embryo to another person is a big ethical problem, and it takes at least three, sometimes up to a dozen, to get enough cells to transplant into one side of a patient’s brain. Since it cannot be supplied in a predictable manner, it is difficult to clinically realize Parkinson’s disease treatment in this way.
Most of the clinical trials currently in progress use stem cells, not embryos directly, and are in the early stage, Phase 1 and Phase 2. Stem cells are undifferentiated cells. Numerous cells constituting the human body are already differentiated and perform roles and functions as part of forming tissues and organs. Unlike most cells, stem cells are not yet differentiated, so they can proliferate and differentiate into other types of cells depending on the environment. The origin of stem cells is diverse.
A number of clinical trials for Parkinson’s disease using stem cells derived from bone marrow or umbilical cord, embryonic stem cells, and ‘inducing dedifferentiation’ stem cells are in progress. As in any case, no stem cell is perfect for regenerative therapy, and each has its pros and cons. For example, depending on the source of the stem cells, there are cases in which there is a need to be concerned regarding immune rejection reactions following transplantation, and there are cases in which there is a stochastic possibility of cells proliferating and forming tumors following transplantation even though immune rejection reactions are not a concern. have.
In particular, clinical trials using embryonic stem cells derived from embryos are attracting attention. A clinical trial of differentiating embryonic stem cells into dopaminergic neurons and transplanting them into Parkinson’s disease patients has been underway since 2021 by Cornell University and Blue Rock Therapeutics in the U.S. started in 2022.
In 2006, Professor Yamanaka of Kyoto University in Japan and others developed a ‘dedifferentiation induction’ technology that initializes differentiated adult cells as if formatting a computer and turns them into stem cells. Using this technology, Professor Kim Kwang-soo of Harvard University and others took skin cells from a 69-year-old Parkinson’s disease patient, converted them into stem cells, and then differentiated them into dopaminergic neurons and transplanted them back to the patient. Kyoto University, which developed the technology, has been conducting clinical trials since 2018 to convert healthy human somatic cells into stem cells and differentiate them into dopaminergic neurons and transplant them into Parkinson’s disease patients.
Aspen Neuroscience of the United States is conducting a clinical trial to convert a patient’s skin cells into stem cells and then differentiate them into dopaminergic neurons and transplant them back to the patient. An American company with a rather ambiguous name, ‘International Stem Cell Company’, announced that it had already completed the ‘world’s first’ clinical trial in Australia, not the United States, in which dedifferentiation-induced stem cells were transplanted into Parkinson’s disease patients in 2021. , details are not known.
