By Cell Stem Cell
Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs). Before these cells can be used for cell replacement therapy in Parkinson’s disease (PD), it is important to verify their functional properties and efficacy in animal models. Here we provide a comprehensive preclinical assessment of hESC-derived midbrain dopamine neurons in a rat model of PD. We show long-term survival and functionality using clinically relevant MRI and PET imaging techniques and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal dopamine neurons. Furthermore, we show that hESC-derived dopamine neurons can project sufficiently long distances for use in humans, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures. This provides strong preclinical support for clinical translation of hESC-derived dopamine neurons using approaches similar to those established with fetal cells for the treatment of Parkinson’s disease.
Cell replacement therapy in Parkinson’s disease (PD) is based on the premise that transplanted midbrain dopamine (DA) neurons can restore dopaminergic neurotransmission when transplanted to the DA-depleted striatum, providing a functionally efficient substitute for the neurons that are lost in the disease. Clinical trials using cells derived from human fetal ventral mesencephalon (VM) have shown that transplanted DA neurons can functionally reinnervate the denervated striatum, restore DA release, and at least in some PD patients, provide substantial long-term clinical improvement (Barker et al., 2013,Kefalopoulou et al., 2014). However, the use of tissue from aborted human embryos presents several ethical and logistical issues that hamper the effective translation of fetal tissue transplantation as a realistic therapeutic option.
In order to move to large-scale clinical applications, a readily available, renewable, and bankable source of cells with the potential to differentiate into fully functional DA neurons after transplantation is an absolute requirement. Among the different stem cell sources available, human pluripotent stem cells, in particular human embryonic stem cells (hESCs), have advanced the furthest (Lindvall and Kokaia, 2009, Barker, 2014). Using protocols entirely based on extrinsic patterning cues that mimic fetal midbrain development, it is now possible to generate DA neurons with an authentic midbrain phenotype from human pluripotent stem cells that survive transplantation and that can restore motor deficits in animal models of PD (Doi et al., 2014, Kirkeby et al., 2012a,Kriks et al., 2011).
However, a number of crucial issues need to be addressed in preclinical studies before these cells can be considered for clinical use: it is important to verify that their functional efficacy is robust, reproducible, and stable over significant time periods; that the transplanted cells have the capacity to grow axons and reinnervate the DA-denervated host striatum over distances that are relevant for the size of the human brain; and that they function with equal potency to human fetal VM DA neurons that have previously been used in clinical trials (Barker, 2014).
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