Non-immunogenic Induced Pluripotent Stem Cells, a Promising Way Forward for Allogenic Transplantations for Neurological Disorders

Abstract

Neurological disorder is a general term used for diseases affecting the function of the brain and nervous system. Those include a broad range of diseases from developmental disorders (e.g., Autism) over injury related disorders (e.g., stroke and brain tumors) to age related neurodegeneration (e.g., Alzheimer's disease), affecting up to 1 billion people worldwide. For most of those disorders, no curative treatment exists leaving symptomatic treatment as the primary mean of alleviation. Human induced pluripotent stem cells (hiPSC) in combination with animal models have been instrumental to foster our understanding of underlying disease mechanisms in the brain. Of specific interest are patient derived hiPSC which allow for targeted gene editing in the cases of known mutations. Such personalized treatment would include (1) acquisition of primary cells from the patient, (2) reprogramming of those into hiPSC via non-integrative methods, (3) corrective intervention via CRISPR-Cas9 gene editing of mutations, (4) quality control to ensure successful correction and absence of off-target effects, and (5) subsequent transplantation of hiPSC or pre-differentiated precursor cells for cell replacement therapies. This would be the ideal scenario but it is time consuming and expensive. Therefore, it would be of great benefit if transplanted hiPSC could be modulated to become invisible to the recipient's immune system, avoiding graft rejection and allowing for allogenic transplantations. This review will focus on the current status of gene editing to generate non-immunogenic hiPSC and how these cells can be used to treat neurological disorders by using cell replacement therapy. By providing an overview of current limitations and challenges in stem cell replacement therapies and the treatment of neurological disorders, this review outlines how gene editing and non-immunogenic hiPSC can contribute and pave the road for new therapeutic advances. Finally, the combination of using non-immunogenic hiPSC and in vivo animal modeling will highlight the importance of models with translational value for safety efficacy testing; before embarking on human trials.

Pluripotent Stem Cells for Spinal Cord Injury Repair

“…The results of these studies will probably help clarifying which is the most optimal source for the development of large-scale therapies in humans. The banking of fully characterized HLA-matched/ablated ESC and iPSC lines produced under cGMP conditions will allow the use of the same lines in both preclinical and clinical studies, favoring standardization and fostering the development of valid therapeutic options for SCI patients in the future (reviewed in [ 84 , 85 ]).…”

Engineered human brown adipocyte microtissues improved glucose and insulin homeostasis in high fat diet-induced obese and diabetic mice

“…Recent clinical studies showed autologous hiPSCs-derived dopaminergic neurons, and retinal cells were safe and effective in treating Parkinson's [80] and macular degeneration [79], respectively, indicating the coming of the hiPSCs-based personalized medicine era. Alternatively, universal hiPSCs can be engineered, for instance, via inactivating major histocompatibility complex (MHC) class I and II genes and overexpressing CD47 or/and PD-L1 [80][81][82][83]. The derivatives of universal hiPSCs are hypoimmunogenic and can be prepared at large scales as "off-the-shelf" allogeneic products.…”

Human Neural Stem Cells for Cell-Based Medicinal Products

“…Establishment of iPSC lines is time-consuming and requires trained operators but once the PSC cells are obtained they are easy to grow, allowing safe production of many cell doses. [ 60 , 61 , 62 , 64 , 65 , 66 , 67 , 68 , 71 , 74 , 95 ] ESC-NSC Only confirmed in animal models. Turmorigenic risk due to potential PSC residues.…”

“…Although at first iPSC were envisioned to be used in an autologous setting, soon researchers realized that the generation of iPSC under GMP conditions (required for clinical use) for a single patient, is time-consuming, expensive, and hardly viable, and therefore, most clinical trials with iPSC-derived products are being performed in an allogeneic setting [ 63 ]. The immunological reaction triggered by allogeneic iPSC-NSC can be overcome by co-treatment with immunosuppressant drugs, use of HLA-matched iPSC or HLA ablated iPSC by gene-editing technologies such as CRISPR (reviewed in [ 64 , 65 ]). To facilitate the search for compatible donors and foster the development of cell therapies with iPSC-derived products, iPSC banks with common HLA haplotypes are being created at different locations such as Japan [ 66 ], the United Kingdom [ 67 ], or the Republic of Korea [ 68 ].…”