Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

Abstract

Neurodegenerative disorders such as Parkinson's (PD) and Huntington's disease (HD) are characterized by a selective detrimental impact on neurons in a specific brain area. Currently, these diseases have no cures, although some promising trials of therapies that may be able to slow the loss of brain cells are underway. Cell therapy is distinguished by its potential to replace cells to compensate for those lost to the degenerative process and has shown a great potential to replace degenerated neurons in animal models and in clinical trials in PD and HD patients. Fetal-derived neural progenitor cells, embryonic stem cells or induced pluripotent stem cells are the main cell sources that have been tested in cell therapy approaches. Furthermore, new strategies are emerging, such as the use of adult stem cells, encapsulated cell lines releasing trophic factors or cell-free products, containing an enriched secretome, which have shown beneficial preclinical outcomes. One of the major challenges for these potential new treatments is to overcome the host immune response to the transplanted cells. Immune rejection can cause significant alterations in transplanted and endogenous tissue and requires immunosuppressive drugs that may produce adverse effects. T-, B-lymphocytes and microglia have been recognized as the main effectors in striatal graft rejection. This review aims to summarize the preclinical and clinical studies of cell therapies in PD and HD. In addition, the precautions and strategies to ensure the highest quality of cell grafts, the lowest risk during transplantation and the reduction of a possible immune rejection will be outlined. Altogether, the wide-ranging possibilities of advanced therapy medicinal products (ATMPs) could make therapeutic treatment of these incurable diseases possible in the near future.

Molecular Components of Store-Operated Calcium Channels in the Regulation of Neural Stem Cell Physiology, Neurogenesis, and the Pathology of Huntington’s Disease

“…Moreover, in vitro differentiated human striatal progenitors, which were transplanted into the striatum from a rat model of HD matured and integrated into host circuits ( Besusso et al, 2020 ). Additionally, other cell types, such as mesenchymal stem cells, are being administrated intravenously to HD patients ( Salado-Manzano et al, 2020 ).…”

Bringing Advanced Therapies for Parkinson’s Disease to the Clinic: An Analysis of Ethical Issues

“…Device-aided therapies are not risk-free. In DBS, electrodes are surgically implanted into the subthalamic nucleus and globus pallidus —a procedure associated with adverse effects such as the worsening of cognitive, motor or psychiatric symptoms and cerebral hemorrhages or stroke [ 16 ]. The mechanisms behind the underlying efficacy of DBS are not well understood [ 17 ], and unexpected harms can sometimes be induced [ 18 ].…”

“…The main task for ATMP-based therapies is to provide such restoring possibilities. To date, the biggest potential for PD treatment using ATMPs is within stem cell-based therapy [ 8 ], distinguished by its potential to replace nerve cells to compensate for those lost in the degenerative process [ 16, 27 ]. To date this approach remains experimental and a number of first-in-human clinical trials (CTs) using cells derived from both human embryonic stem cells and induced pluripotent stem cells are on the way [ 28, 29 ].…”

“…To date this approach remains experimental and a number of first-in-human clinical trials (CTs) using cells derived from both human embryonic stem cells and induced pluripotent stem cells are on the way [ 28, 29 ]. The road to clinical application of certain types of cell-based therapies is estimated to be long, entailing challenges in controlling differentiation into defined subtypes of cells, reducing the immune response that occurs in the central nervous system [ 16 ] and assuring that the produced cells are safe (e.g., with reduced risks of tumorigenesis [ 15 ]) and efficacious, as well as Good Manufacturing Practice –compliant, which is necessary for their use in patients [ 28 ]. Another significant advance is in the area of gene therapy where a single injection of a gene into a nerve cell could give rise to a continuous production of the associated protein [ 8 ], which could potentially stimulate dying nerve cells to regrow and thus reverse the progression of PD [ 8 ].…”

Mesenchymal Stem Cells in Premature Ovarian Insufficiency: Mechanisms and Prospects

“…Notably, paracrine effectors of their secretome, including cytokines, growth factors, and miRNA, can be transferred to target cells in damaged tissues, resulting in long-term effects ( Ranganath et al, 2012 ; Sajeesh et al, 2020 ). Several studies have explored efficacy of MSCs-mediated therapy in various diseases owing to their unique characteristics ( Martinez-Carrasco et al, 2019 ; Oliva, 2019 ; Salado-Manzano et al, 2020 ). Transplantation of MSCs is a good option for fundamental POI treatment owing to their low immunogenicity, broad sources, and availability.…”