Unleashing the Power of Induced Pluripotent stem Cells in in vitro Modelling of Lesch-Nyhan Disease

Lesch-Nyhan disease (LND) is a monogenic rare neurodevelopmental disorder caused by a deficiency in hypoxanthine–guanine phosphoribosyltransferase (HPRT), the key enzyme of the purines salvage pathway. Beyond its well-documented metabolic consequences, HPRT deficiency leads to a distinctive neurobehavioral syndrome characterized by motor disabilities, cognitive deficits, and self-injurious behavior. Although various cell and animal models have been developed to investigate LND pathology, none have adequately elucidated the underlying mechanisms of its neurological alterations. Recent advances in human pluripotent stem cell research and in vitro differentiation techniques have ushered in a new era in rare neurodevelopmental disorders research. Pluripotent stem cells, with their ability to propagate indefinitely and to differentiate into virtually any cell type, offer a valuable alternative for modeling rare diseases, allowing for the detection of pathological events from the earliest stages of neuronal network development. Furthermore, the generation of patient-derived induced pluripotent stem cells using reprogramming technology provides an opportunity to develop a disease-relevant model within the context of a patient-specific genome. In this review, we examine current stem cell-based models of LND and assess their potential as optimal models for exploring key pathological molecular events during neurogenesis and for the discovering novel treatment options. We also address the limitations, challenges, and future prospects for improving the use of iPSCs in LND research. Graphical Abstract: (Figure presented.)