【2023 學術演講】Human Pluripotent Stem Cells in Parkinson’s Disease: The dream of rebuilding a brain pathway

2023 神醫中心學術演講2  (實體) 

日期 : 3月 1日星期三

時間 : 下午2:00  

地點 : 國衛院竹南院區/ 行政大樓B1第4會議室

主題 : Human Pluripotent Stem Cells in Parkinson’s Disease: The dream of rebuilding a brain pathway

講師 : William J. Freed. Ph.D.

Adjunct Professor, Department of Biology, Lebanon Valley College, Annville, PA,U.S.A.

Retired Senior Investigator, National Institute on Drug Abuse, NIH, U.S.A.

報名連結


視訊系統 Webex  : 會議連結     

會議號: 2512 073 7164   密碼: 0301


摘要

There has been a great deal of interest in transplantation of dopamine (DA)-producing cells for therapy of Parkinson’s disease, an enterprise that has been ongoing for more than 40 years. Initially fetal DA neurons were used, but later other cell types such as adrenal chromaffin cells, and more recently cells derived from human pluripotent stem cells (hPSC) have been the focus of attention. We tend to think of this problem in fairly simple terms, as essentially a matter of finding appropriate cells and placing them in appropriate locations.

There are several persistent problems and limitations of DA cell transplantation in Parkinson’s disease. Almost all pre-clinical work has been based on rodent studies, often lacking appropriate control groups. There have been very few controlled studies in subhuman primates. Use of sub-human primates is severely limited by expense and other difficulties. Thus, in the long term an alternative large animal model is essential.

Some of the basic limitations of dopamine neuron transplantation have not been addressed, including the limited ability of transplanted neurons to extend axons in mature hosts, poor survival of transplanted cells, and lack of efficacy for non-motor symptoms such as apathy or
amotivation. Transplantation of dopamine neurons in mature animal hosts does not restore deficits in motivated behavior.

Clinical studies of human fetal DA neuron transplantation have observed a high frequency of dyskinesias and side effects including confusion and possibly hallucinations of unknown cause. Politis and coworkers (2012) reported that transplanted patients show long-term progression of non-motor symptoms. There is a possibility that only motor function per secan be improved by transplantation while other symptoms, especially apathy and anhedonia, will continue to progress to debilitating levels.

There are now several methods of differentiating DA neurons from hESC and hiPSC which have the potential to facilitate neural transplantation therapy. For DA neurons derived from hPSC, however, additional potential problems arise. These are a possibility of genetic instability during reprogramming or maintenance, inclusion of undesired cell types, and identifying an appropriate stage or form of differentiation. Genetic variations in hPSC lines have profound effects on differentiation capacity. There are also concerns that DA neurons derived from hPSC are not as effective as fetal cells. DA neurons alone may not function optimally in the absence of appropriate support cells such as astrocytes.

Treatment of Parkinson’s disease by DA neuron transplantation is ultimately a complex problem. Mere transplantation of DA neurons is not likely to restore DA circuits, and the  reasons that transplantation restores function are not well understood. Nevertheless, the availability of hPSC allows for genetic modification, so that ultimately DA neurons can be customized for transplantation. Thus, it is likely that transplantation for Parkinson’s disease will continue to evolve over many years. Mere availability of stem cell-derived DA neurons may not be sufficient to allow for an effective or useful therapy


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更新 : 2023-02-22

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