Generating and transplanting dopamine-generating neurons into the brains of Parkinson's disease patients, to replace the cells destroyed by processes such as aggregation of α-synuclein, is one of the longer-running lines of development in modern cell therapy research. While the regenerative medicine community has advanced a long way past the first, mixed attempts at treating Parkinson's disease in this way, a great deal of work yet lies ahead in order to produce a reliable approach to the replacement of damaged cells. Most of the challenges are relevant to all attempts to introduce new, functional cell populations into the aging body: ensuring the cells survive; preventing the age-damaged environment from overwhelming any benefits that are produced; establishing cost-effective sources of cells, preferably derived from the patient's own tissues.
Current approaches to cell replacement therapy in Parkinson's disease (PD) are strongly focused on the dopamine system, with the view that restoring dopaminergic inputs in a localized and physiologic manner will provide superior benefits in terms of effect and longevity compared with oral medication. Experience using transplants of fetal tissue containing dopaminergic cell precursors has provided valuable proof that the approach is feasible, and that engrafted cells can survive and function over many years. However, multiple drawbacks and procedural complications are recognized in using fetal cells.
Recent strides in stem cell technology now make it possible to overcome some of the barriers associated with fetal tissue. The first generation of stem cell-derived dopaminergic neurons now in the pipeline is predicted to perform at least at an equivalent level to human fetal cells, but in a more robust and reproducible manner, providing a stable, expandable, and readily accessible cell source for transplantation. As such the therapy is expected to provide a better way of treating the dopamine responsive features of PD using a targeted, physiological delivery of dopamine to the striatum, but it is not a disease modifying treatment, nor a cure.
Many questions remain to be addressed. For example, PD pathology is not cell-autonomous, and the spread of pathology potentially affecting graft function is an oft-repeated although unsubstantiated objection to cell therapy. While current evidence supports absence of any major effect, it does raise the question of whether a combinatorial therapy comprising grafting and, for example, a biologic or small molecule to abrogate spread of alpha-synuclein pathology would be desirable.
In this article we have only discussed use of dopaminergic cells, whereas a stem cell source allows growth of any cell type. Other neural networks would be much more difficult to rebuild, but it is tempting to speculate that, for example, cholinergic neurons could be helpful in addressing cognitive function, or balance. There is a long road ahead in demonstrating how well stem cell-based reparative therapies will work, and much to understand about what, where, and how to deliver the cells, and to whom. But the massive strides in technology over recent years make it tempting to speculate that cell replacement may play an increasing role in alleviating at least the motor symptoms, if not others, in the decades to come.