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HSC-based therapies for LSDs: understanding the modalities of cell replacement in the LSD brain for improving therapeutic efficacy

Final Report Summary - HSCSFORLSDBRAIN (HSC-based therapies for LSDs: understanding the modalities of cell replacement in the LSD brain for improving therapeutic efficacy)

This project was intended at generating strategies for enhancing the efficacy of hematopoietic stem and progenitor cell gene therapy approaches for lysosome al storage disorders, severe neurodegenerative inherited disease of childhood. These strategies were to be defined base on an increased understanding of the mechanisms of contribution of the transplanted cells to brain myeloid/microglia cell populations. This could be achieved by developing the specific aims of the project. In particular, we obtained information on the crucial cells for this process, namely the endogenous progenitors of microglia, residing in the brain, and their counterpart within hematopoietic stem and progenitor cell pool. These cells constitute the key of our approach, that is based on the specific ablation of the former to enable the engraftment of the latter upon transplantation, with generation of a mature tissue progeny resembling microglia. Methods to do this were optimized along the course of the project and will be progressively introduced into a path to clinical translation to optimize treatment of LSD patients. Some of these innovations will be first tested in humans in a Phase 1/2 trial of HSC gene therapy for a form of neuronal ceroid lipofuscinosis that is being prepared based on the evidences generated in the ERC project.