P036
Development of advanced therapies and 2D and 3D in vitro models generated from ultra-rare variants and VUS in rare neurodevelopmental disorders
A Salgado-Roo(1,2) S Veiga-Rúa(1,2) L F Pedrera-Garbayo(1,2) M Hernández-Gamarra(1,2) A Carracedo(1,2,3,4) C Allegue(1,2,3)
1:Genomic Medicine, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, Santiago de Compostela, 15706, Spain; 2:C005, Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, 15706, Spain; 3:U711, Center for Biomedical Network Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, 28029, Spain; 4:Fundación Pública Galega de Medicina Xenómica (FPGMX), Hospital Clínico Universitario, Santiago de Compostela, 15706, Spain.
The main objective of this project is to investigate the role of ultra-rare and genomic variants of uncertain significance (VUS) in patients with rare neurodevelopmental disorders such as Lafora Disease (ORPHA:501) or GABRB3-related syndromes. Additionally, advanced therapeutic screening strategies will be carried out on cellular models derived from these patients, including genome editing and mRNA delivery.
These models will allow for improved genetic counseling for patients and their families, as well as a deeper understanding of the molecular mechanisms underlying the disease and identification and screening of therapeutic targets for the development of advanced therapies.
The specific objectives of the project include: selecting rare genomic variants related to LD and other rare neurodevelopmental disorders; designing and setting up assays to model these variants on human induced pluripotent stem cells (hiPSCs) using CRISPR-Cas9; differentiating hiPSCs from patients into 2D and 3D cultures; and screening advanced therapeutic strategies based on gene therapy and mRNA delivery on the generated models.
This project aims to contribute to the understanding of the pathophysiology of neurodevelopmental disorders and provide a foundation for the development of targeted therapies for patients.