Cell Replacement Therapy for Parkinson's Disease

How Close Are We to the Clinic?

Javier Ganz; Nirit Lev; Eldad Melamed; Daniel Offen


Expert Rev Neurother. 2011;11(9):1325-1339. 

In This Article

Explored Cells for CRT

Different cell types have been proposed as viable candidates to generate mature nigrostriatal neurons suitable for CRT in PD. Ideally, grafted DA neurons into the substantia nigra should be able to reconstruct the nigrostriatal pathway, re-establishing the DA modulation of the basal ganglia circuit and promoting regulatory inputs to the DA-secreting neurons that allow compensatory mechanisms, such as feedback.[28] This 'ideal' concept mentioned above is a description of how DA neurons should perform in a best case scenario. This potential scenario can only be achieved through the transplantation of the new cells into the substantia nigra area with the consequent synaptic re-establishment, but could not be achieved through striatal transplantation. The produced DA neurons must show regulated DA synthesis and release, be capable of growth of DA projections through the nigrostriatal pathway in order to innervate the striatum, induce a re-establishment of a dense terminal network throughout the striatum and, of course, a successful integration of the transplanted neurons into the host neural circuitries is needed. Moreover, the produced DA neurons should exhibit molecular, morphological and electrophysiological properties of substantia nigra neurons, harboring the capacity to reverse motor deficits and be able to survive for decades in the human brain.[40] Several sources of catecholaminergic cells, including autografts of the adrenal medulla and allografts or xenografts of mesencephalic fetal tissue, were successfully assessed in animal models, but their clinical translation has yielded poor results and much controversy. While the fetal tissue trials were ongoing, researchers explored a variety of alternative cell sources of DA neurons, including other animal species, human cadaveric tissue and autologous transplantation. The objective was to overcome the practical and ethical limitations of using human fetal cells for large-scale clinical applications. Porcine mesencephalic DA fetal neurons were grafted into a rat model of PD.[41] The transplanted cells survived and motor improvements have been reported. In addition, a Phase I clinical trial[42] and a similar double-blind placebo-controlled study were performed, but no significant improvements in PD symptoms were documented.[42,43] Mesencephalic fetal porcine cells presented similar challenges to success as human fetal tissue graft, adding the xenograft immunological complications.[44] Human retinal epithelial cells obtained from cadaveric tissue were also tested as candidates owing to the L-DOPA mechanism those cells harbor. Preclinical trials in rats and monkeys through intrastriatal transplantation reported cell survival, as well as motor function improvements.[45,46] A pilot human study showed UPDRS improvements and a double-bind Phase IIb clinical trial was initiated, but was suspended for not reaching the primary study requirements.[47] After the failed adrenal medulla transplantation trials carried out by Backlund[23] and Madrazo,[48] more autologous cell sources were explored. Autologous sympathetic ganglion cells grafts showed improvements in transplanted rats;[49] however, in a trial of 35 patients this procedure did not show significant improvements.[50] Carotid cell bodies or glomus type I cells, which are located near the carotid artery bifurcation, are derived from the neural crest and release a variety of neurotransmitters, including acetylcholine, ATP and dopamine.[51] Striatal transplantation of carotid cell bodies was also attempted and showed an improved motor behavior in rats[52] and monkeys;[53] however, a clinical trial that showed initial success did not end with encouraging results.[54]

Owing to recent biological breakthroughs associated with advanced technologies, new cell sources, such as stem cells, have emerged (Figure 1). It is important to bear in mind that the concept of the 'perfect' cell source for DA neuron generation might be a utopic concept – that is, each type of stem cell possesses specific advantages and disadvantages. Unique methodologies have been developed in order to coax specific differentiation processes into DA neurons, including genetic manipulation, exposure to a variety of morphogenetic factors or chemical compounds. To date, a host of different cells has been explored in the search for new DA neuron sources. Hereafter, we will review the experiences gained through the years with some of these cells, towards an efficient and secure DA neuron generation.

Figure 1.

Stem cell sources for dopaminergic neuron generation. Representative scheme of the different stem cells sources explored on the road to dopaminergic neuron generation. To date, dopaminergic neurons have been successfully generated from neural stem cells, mesenchymal stem cells, adult cells through induced pluripotent cells, and embryonic stem cells. Recent discovery of inducible neurons, which directly convert adult fibroblasts into functional neurons [96], may also serve as a suitable source for dopaminergic neuron generation, but no work has been carried out in regard to this objective. iN: Inducible neuron.