Abstract and Introduction
Cell replacement therapy (CRT) offers great promise as the future of regenerative medicine in Parkinson's disease (PD). Three decades of experiments have accumulated a wealth of knowledge regarding the replacement of dying neurons by new and healthy dopaminergic neurons transplanted into the brains of animal models and affected patients. The first clinical trials provided the proof of principle for CRT in PD. In these experiments, intrastriatal transplantation of human embryonic mesencephalic tissue reinnervated the striatum, restored dopamine levels and showed motor improvements. Sequential controlled studies highlighted several problems that should be addressed prior to the wide application of CRT for PD patients. Moreover, owing to ethical and practical problems, embryonic stem cells require replacement by better-suited stem cells. Several obstacles remain to be surpassed, including identifying the best source of stem cells for A9 dopaminergic neuron generation, eliminating the risk of tumor formation and the development of graft-induced dyskinesias, and standardizing dopaminergic cell production in order to enable clinical application. In this article, we present an update on CRT for PD, reviewing the research milestones, various stem cells used and tailored differentiation methods, and analyze the information gained from the clinical trials.
Parkinson's disease (PD) is a chronic progressive neurodegenerative disease that affects over 1% of the population over 65 years of age and has been positioned as the second most common neurodegenerative disorder after Alzheimer's disease. The cardinal symptoms of PD include resting tremor, rigidity, bradykinesia and postural instability. Symptoms that appear later also include non-motor signs, such as autonomic, sensory, psychiatric and cognitive impairments. The clinical motor dysfunction observed in PD is primarily the consequence of a progressive and selective degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta of the ventral midbrain, resulting in a severe deficiency of dopamine in the nigrostriatal pathway affecting the striatum. Restoring dopamine levels by levodopa therapy is still the cornerstone of PD treatment; however, long-term treatment results in serious motor and psychiatric side effects, a process known as the 'L-DOPA paradox'. Other treatments such as DA agonists, metabolic enzyme inhibitors and deep brain stimulation aid in management of PD patients; however, all these treatment options still have clinical limitations. Despite the availability of effective symptomatic drugs, there is currently no cure for PD and almost every attempt to slow the neuronal loss or stop disease progression has failed.
Cell replacement therapy (CRT) has emerged as an attractive strategy for regenerative medicine in PD. As 'proof of principle', it was demonstrated in several clinical studies that have been performed that replacement of lost DA neurons can improve motor symptoms of PD patients. Although this approach has been investigated for over three decades, several obstacles have emerged and prevented its wide application in PD therapy, diminishing the initial excitement. New approaches are currently being developed and tested further in order to achieve a substantial improvement in CRT, enabling future use of these promising therapies for PD patients. The aim of this manuscript is to review the cutting edge of current research on CRT strategies in PD, as well as to describe the experience that has accumulated from clinical transplantation trials in PD patients.