Replacing what’s lost: a new era of stem cell therapy for Parkinson’s disease

Abstract

BackgroundStem cells hold tremendous promise for regenerative medicine because they can be expanded infinitely, giving rise to large numbers of differentiated cells required for transplantation. Stem cells can be derived from fetal sources, embryonic origins (embryonic stem cells or ESCs) or reprogrammed from adult cell types (induced pluripotent stem cells or iPSCs). One unique property of stem cells is their ability to be directed towards specific cell types of clinical interest, and can mature into functional cell types in vivo. While transplantations of fetal or ESC-derived tissues are known to illicit a host immunogenic response, autologous transplantations using cell types derived from one’s own iPSCs eliminate risks of tissue rejection and reduce the need for immunosuppressants. However, even with these benefits, cell therapy comes with significant hurdles that researchers are starting to overcome. In this review, we will discuss the various steps to ensure safety, efficacy and clinical practicality of cell replacement therapy in neurodegenerative diseases, in particular, Parkinson’s disease.Main bodyParkinson’s disease (PD) results from a loss of dopaminergic neurons from the substantia nigra and is an ideal target for cell replacement therapy. Early trials using fetal midbrain material in the late 1980s have resulted in long term benefit for some patients, but there were multiple shortcomings including the non-standardization and quality control of the transplanted fetal material, and graft-induced dyskinesia that some patients experience as a result. On the other hand, pluripotent stem cells such as ESCs and iPSCs serve as an attractive source of cells because they can be indefinitely cultured and is an unlimited source of cells. Stem cell technologies and our understanding of the developmental potential of ESCs and iPSCs have deepened in recent years and a clinical trial for iPSC-derived dopaminergic cells is currently undergoing for PD patients in Japan. In this focused review, we will first provide a historical aspect of cell therapies in PD, and then discuss the various challenges pertaining to the safety and efficacy of stem cell-based cell transplantations, and how these hurdles were eventually overcome.ConclusionWith the maturity of the iPSC technology, cell transplantation appears to be a safe and effective therapy. Grafts in non-human primates survive and remain functional for more than 2 years after transplantation, with no signs of tumorigenesis, indicating safety and efficacy of the treatment. However, immunosuppressants are still required because of the lack of “universal stem cells” that would not evoke an immune response. The results of ongoing and upcoming trials by a global consortium known as GForce-PD would be highly anticipated because the success of these trials would open up possibilities for using cell therapy for the treatment of PD and other degenerative diseases.

Autophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act

“…However, none of these are capable of delaying or stopping the progression of the disease. Other promising therapies, some of them yet not tested in humans, have been developed over recent years, including stem cell-based approaches (stem cell and induced pluripotent stem cells derived from patients' fibroblasts have emerged as a powerful tool to obtain a renewable source of dopaminergic neurons that can integrate in the brain [ 560 , 561 ]), the use of neurotrophic factors (e.g., BDNF and GDNF (glial-derived neurotrophic factor)), antioxidants as neuroprotective compounds (e.g., NOS inhibitors, iron chelators, and NRF2 activators [ 438 , 441 , 562 , 563 ]), gene therapy (e.g., viral-gene expression of TH, AADC, or VMAT2 to induce dopamine release, or NURR1 expression which appears to have a neuroprotective role), and immunotherapy (e.g., for the clearance of α -synuclein aggregates) [ 564 – 567 ]. In addition, another divergent approach is enhancing the autophagy process.…”

Current Status of Stem Cell-Derived Therapies for Parkinson’s Disease: From Cell Assessment and Imaging Modalities to Clinical Trials

“…Generally, stem cells are differentiated into specific nigra A9 DA neurons in large quantities prior to PD transplantation. This step has been thoroughly reviewed by many articles such as in Fan et al (2020) and, thus, will not be further discussed here. However, we focus on developments in technology in cell assessment of differentiated DA neurons.…”

“…Moreover, common positive markers used to isolate high-quality DA progenitor cells include EN1 and SPRY1 ( Simon et al, 2001 ; Alberi et al, 2004 ; Kirkeby et al, 2017a ); Nurr1 ( Le et al, 1999 ); FOXA2, LMX1B, and MSX1 ( Andersson et al, 2006 ; Chung et al, 2011 ), and the bicoid-related homeodomain factor Ptx3/Pitx3 ( Hargus et al, 2010 ). It is noteworthy that some discrepancies have been found with the requirement for the presence of floor plate-specific cell surface marker CORIN expression ( Ono et al, 2007 ; Chung et al, 2011 ; Kriks et al, 2011 ; Kirkeby et al, 2012 , 2017a ; Doi et al, 2014 ; Arenas et al, 2015 ; Fan et al, 2020 ). A more recent study has identified a cell surface marker integrin-associated protein (IAP, CD47) as a positive marker for FOXA2-positive DA progenitor cells ( Lehnen et al, 2017 ).…”

Neuronal Reprogramming for Tissue Repair and Neuroregeneration

“…A number of clinical trials for iPSC-derived products have been initiated for the treatment of neurodegenerative diseases. In Japan, a Phase I/II clinical trial led by Jun Takahashi is currently testing the efficacy of using iPSC-derived dopaminergic progenitor cells to treat Parkinson’s disease [ 110 , 111 ]. In the eye, there are promising results for early trials of RPE replacement therapy, with several ongoing phase I/II clinical trials for PSC-derived RPE replacement [ 112 , 113 , 114 , 115 ].…”