Development and Standardization of Motor Neuron Differentiation from iPSCs for the Study of Amyotrophic Lateral Sclerosis (ALS)

Abstract

One of the major challenges encountered in translational research applied to rare neurodegenerative diseases (NDs), such as Amyotrophic Lateral Sclerosis (ALS), is the functional evaluation of new variants potentially associated with these diseases. Novel gene variants of uncertain significance (VUS) are often identified in patients with NDs, highlighting the need for functional validation to establish their causal association with disease. One strategy to address this need is the generation of patient-specific models for gene screening and therapeutic component testing, presenting a significant opportunity for innovation in this field. To meet this demand, this project aims to optimize the differentiation of motor neurons for an in vitro model of Amyotrophic Lateral Sclerosis (ALS) by expressing heterologous transcription factors to assess the contribution of patient-specific VUS in cranial and spinal motor neurons derived from iPSCs. In this context, the student will receive theoretical and practical training in the integration of technologies at the interface of genetic engineering, based on CRISPR-Cas9 and PiggyBAC in human-induced pluripotent stem cells (iPSCs). The approach the student will develop alongside our research group offers an innovative solution to accelerate the modeling, discovery, and delivery of potential translational therapies in patient-specific in vitro models, which can be easily adapted and applied to meet the functional validation needs of rare human genetic diseases beyond ALS. (AU)