Author: Malin Parmar, Shane Grealish and Claire Henchcliffe
Cell- replacement therapies have long been an attractive prospect for treating Parkinson disease. However, the outcomes of fetal tissue- derived cell transplants in individuals with Parkinson disease have been variable, in part owing to the limitations of fetal tissue as a cell source, relating to its availability and the lack of possibility for standardization and to variation in methods.
Advances in developmental and stem cell biology have allowed the development of cell- replacement therapies that comprise dopamine neurons derived from human pluripotent stem cells, which have several advantages over fetal cell- derived therapies. In this Review, we critically assess the potential trajectory of this line of translational and clinical research and address its possibilities and current limitations and the broader range of Parkinson disease features that dopamine cell replacement based on generating neurons from human pluripotent stem cells could effectively treat in the future.
Parkinson disease (PD) is a progressive neurodegenerative disorder that is characterized by relatively focal degeneration of mesencephalic dopamine (mesDA) neurons, the cell bodies of which are located within the substantia nigra pars compacta in the ventral mesencephalon (VM). The associated loss of axonal projections and subsequent deficit in DA release onto the medium spiny neurons of the striatum results in disability, particularly bradykinesia, resting tremor and muscle rigidity. The fact that many of the key motor symptoms and signs of PD result from the loss of mesDA neurons means that, unlike in many neurodegenerative disorders, replacing just one cell type in a single localized brain region holds promise for relieving some of the significant deficits that affect individuals with PD. As such, PD has long been a trailblazer for cell- replacement therapy.
Initial efforts in this area started more than three decades ago and provided proof- of-principle evidence that DAergic neuron precursor cells isolated from the developing human VM could survive and function in graft recipients with PD when surgically delivered to the putamen, a main target area of mesDA neurons2. However, the use of human fetal VM tissue posed serious limitations (discussed later) that precluded clinical application of a cell- based therapy until recently1. Several notable advances in culturing and differentiating human pluripotent stem cells (hPSCs)3–6 have now allowed the formation of transplantable VM progenitors that mature into DA neurons that are virtually indistinguishable from human fetal mesDA neurons with respect to molecular identity, invivo functionality, potency and target- specific axonal outgrowth7.
On this basis, we refer to the mesDA- like neurons sourced from hPSCs as ‘hPSC- derived mesDA neurons’. The field is now on the verge of using hPSC- derived mesDA neurons instead of fetal cells to provide unlimited numbers of quality- controlled cells for clinical trials as a more robust and available future therapy. Indeed, the international collaborative network GForce- PD (http://www.gforce- pd.com) has enabled several consortia working on stem cell- based DAergic replacement therapy for PD to share their experiences in the design and execution of the first- in-human clinical trial of hPSC- derived mesDA neurons for PD8. The GForce- PD network is continuously growing, and its last meeting was attended by two USA- based, one Europe- based and two Asia- based teams, all at the verge of entering clinical trials. Together, the efforts of these teams and the broader community have catapulted hPSCs for cell- replacement therapy for PD to the forefront of regenerative medicine.
In this Review, we describe the key developments in research into DA cell- replacement therapy for PD so far, as well as current and future research aimed at improv-ing graft function and reproducibility by increasing the survival and purity of mesDA neurons in the graft, accelerating their fate acquisition and/or functional maturation and making them less susceptible to attack by the immune system. Furthermore, we speculate on the trajectory of this line of translational and clinical research and address the broader range of PD features that hPSCs might effectively treat.
Credit: Nature Reviews | Neuroscience