Abstract
The study of neurological disorders often presents with significant challenges due to the inaccessibility of human neuronal cells for further investigation. Advances in cellular reprogramming techniques, have however provided a new source of human cells for laboratory-based research. Patient-derived induced pluripotent stem cells (iPSCs) can now be robustly differentiated into specific neural subtypes, including dopaminergic, inhibitory GABAergic, motorneurons and cortical neurons. These neurons can then be utilized for in vitro studies to elucidate molecular causes underpinning neurological disease. Although human iPSC-derived neuronal models are increasingly regarded as a useful tool in cell biology, there are a number of limitations, including the relatively early, fetal stage of differentiated cells and the mainly two dimensional, simple nature of the in vitro system. Furthermore, clonal variation is a well-described phenomenon in iPSC lines. In order to account for this, robust baseline data from multiple control lines is necessary to determine whether a particular gene defect leads to a specific cellular phenotype. Over the last few years patient-derived neural cells have proven very useful in addressing several mechanistic questions related to central nervous system diseases, including early-onset neurological disorders of childhood. Many studies report the clinical utility of human-derived neural cells for testing known drugs with repurposing potential, novel compounds and gene therapies, which then can be translated to clinical reality. iPSCs derived neural cells, therefore provide great promise and potential to gain insight into, and treat early-onset neurological disorders.
Highlights
Over the last decade, significant advances such as whole exome and genome sequencing have facilitated genetic screening of patients, resulting in an ever-increasing number of inherited human diseases
Since the first human embryonic stem cells (ESCs) were isolated in 1998 (Thomson et al, 1998), the use of pluripotent stem cells (PSCs) has become a new reality in the study of human diseases, offering a challenging but incredibly useful model to move from clinic to bench and potentially vice versa
When approaching the study of neurological diseases using human induced pluripotent stem cell-derived neurons as an in vitro model system, several considerations need to be taken into account, including the accurate generation of truly pluripotent cells, the relative efficiency of neuronal differentiation, and the strengths, utility and limitations of generated neurons
Summary
Significant advances such as whole exome and genome sequencing have facilitated genetic screening of patients, resulting in an ever-increasing number of inherited human diseases. Despite this genetic revolution, the molecular mechanisms downstream of a specific gene mutation or genetic variant remain yet to be fully elucidated for the majority of diseases. Future research priorities must lie in studying such disorders in more depth, to understand the disease, and to develop novel therapies for clinical translation
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