PD and steam cells therapy

PD and steam cells therapy
Mohsen Rezaei Aghdam,^1,*
1. Department of Biological Science, Faculty of Basic Science, Higher Education Institute of Rab-Rashid
Introduction: Parkinson's disease (PD) is a neurodegeneration disorder caused by the destruction of dopaminergic neurons in the midbrain, and the cause of this degradation is not yet known. But factors such as environmental pollution, age, toxins and genetic factors to be involved in this destruction. Cell- replacement therapies showe an attractive prospect for treating PD. With relatively localized neural degeneration, similar to spinal column injury, PD presents a better candidacy for cell therapy when compared to other diffuse degeneration found in Alzheimer’s or Huntington’s Disease.
Methods: Transplantation of midbrain dopaminergic neuron (DA) precursors from allogeneic fetal tissue was performed to the striata of individuals with PD. The first- in-human clinical studies provided proof of concept that tissue could be implanted into the brains of patients with no overt negative effects at the target site of transplantation, but variable clinical benefits were observed. Other sources of cells for transplantation have included autologous adrenal medullary tissue as a source of DA derived from neuroendocrine chromaffin cells, autologous carotid body tissue as a source of DAergic glomus cells and retinal pigmented epithelial cells as a source of levodopa. However, transplants of cells other than authentic fetal ventral mesencephalon (VM) DAergic neurons have failed to demonstrate key requisite properties. In particular, the rationale for transplanting adrenal medullary tissue, which is based on the fact that neuroendocrine chromaffin cells can produce DA, has been questioned. Importantly, the open-label studies demonstrated that fetal VM was the only cell source that conferred the potential for clinical improvement and, notably, for graft survival and function as demonstrated by clinical measures, neuroimaging and post- mortem histo logical analysis. However, the outcomes of fetal tissue-derived cell transplants in individuals with PD 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. Neurosurgical implantation of pluripotent cells poses the risk of an innate immune response and tumorigenesis. Precautions, therefore, must be taken to ensure cell line quality before transplantation. 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 (hPSC), which have several advantages over fetal cell-derived therapies. Current techniques focus on induced pluripotent stem cells (iPSCs) because they can be matched with donors using human leukocyte antigens, thereby reducing the severity and risk of immune rejection. Sourcing cell therapy with iPSC lines provides ethical advantages because these stem cell lines do not require the sacrifice of human zygotes and genetically-specific drug trails can be tested in vitro without lasting damage to patients. Transplantation of hPSC- derived DAergic neuron precursors to the striatum is predicted to generate more robust and consistent outcomes than previously tested regenerative therapies using fetal VM tissue. In hopes of finally slowing the progression of PD or re-establishing function, iPSC lines can ultimately be corrected with gene therapy and used as cell sources for neural transplantation for PD. The first human clinical trial using iPSC cell therapy transplantation for patients with moderate PD was performed in 2018. For cell therapy to be optimized, effective and clinically relevant for a wider range of symptoms, key limitations must be addressed in the future using emerging technologies and new disease insights: as trials progress, optimal and probably individualized dosing and spatial delivery schemes, possibly based on PET biomarkers that quantify and map out existing DA inputs, will improve. In addition, adjunct interventions to increase cell survival, enhance physiological synaptogenesis and promote development of ‘normal’ neuronal controls on the engrafted cells are likely to be put in place. This could be attempted, for example, using gene modification to express neurotrophic or other factors, or by simultaneous delivery of adjunctive therapeutics
Results: Over the past few decades, rapid advances in stem cell technology, including development of robust differentiation protocols and manufacturing processes, have facilitated the development of a first generation of hPSC-derived DA neuron technologies that are now in the pipeline for first- in-human clinical trials. Although there is not yet a valid evidence at a disease-modifying treatment, stem cell technologies have the potential to be at the forefront of such PD treatments in the future.
Conclusion: Over the past few decades, rapid advances in stem cell technology, including development of robust differentiation protocols and manufacturing processes, have facilitated the development of a first generation of hPSC-derived DA neuron technologies that are now in the pipeline for first- in-human clinical trials. Although there is not yet a valid evidence at a disease-modifying treatment, stem cell technologies have the potential to be at the forefront of such PD treatments in the future.
Keywords: Parkinson's disease cell- replacement steam cells