Lysosomal Diseases

Different therapeutic approaches will be tested, and new models will be generated using genome editing by CRISPR/Cas9. For Sanfilippo C syndrome, drug repositioning and substrate reduction treatments based on RNAi will be tested on iPS cell-derived neurons. The possible export of the HGSNAT protein from glial cells to neurons derived from iPS of Sanfilippo C will be studied in co-cultures. The CRISPR/Cas9 system will be used on WT iPSC to generate KO models of Sanfilippo A, B and C. For Gaucher disease, in which the bone disease is refractory to treatment, we will test therapies based on chaperones and other drugs, in osteoblasts derived from patients’ iPS cells, generated in the group. Finally, in the murine models of Niemann-Pick C generated, two therapeutic approaches will be assayed: one of them based on antisense oligonucleotides to prevent the incorporation of a pseudoexon into the mRNA and the other, based on the deletion of the pseudoexon at genomic level by CRISPR/Cas9.The development of new models for those neurological cases that may allow to assay new therapeutic approaches on the cellular type more affected in the pathology (neurons) may have a high impact in the field, and this knowledge may be transferred to the health system. It may be the first step towards future therapeutic approaches and clinical trials for the patients for whom no cure currently exists.