Human Induced Pluripotent Stem Cells in Rare Neurological Disorders: Opportunities and Challenges for Disease Modeling and Drug Discovery.

Rare disease is a condition that affects a small fraction of the population. In most cases, it has a known genetic cause but could also be associated with other contributing factors. As the affected individuals may exhibit diverse symptoms due to the genetic and phenotypic heterogeneity, non- or misdiagnosis of rare diseases is common. Their low incidence and prevalence present an obstacle to developing new therapies despite a major unmet need with only a few treatment options available. This is particularly relevant to rare neurological disorders as there are major difficulties in studying the mechanisms of initiation and progression of the central nervous system (CNS) disorders. Recent advances in biotechnology, specifically the use of human induced pluripotent stem cells (iPSCs) for modeling diseases, have been instrumental in providing a flexible platform that not only reflects the effects of genetic disturbances on the development of CNS disorders but also is capable of providing insights into complex multifactorial disorders. Whether the human iPSCs are harvested from the affected individuals or using the gene-editing tools on cells from healthy individuals, valuable models can now be made available for studying these orphan conditions. In this narrative review, we explore the benefits of using human iPSC models over the existing platforms of other primary cell lines and animal models for the disease modeling and drug discovery and discuss the limitations and future aspects of the iPSC use in the investigation of rare neurological disorders.