Gene therapy for fatal neurodegenerative diseases

Mutations of the granulin (GRN) gene cause reduction or complete absence of progranulin (PGRN) protein. This in turn leads to two fatal neurodegenerative diseases - frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis-11 (CLN11), respectively. Brain microglia cells are the main producers of PGRN and thus play a major role in both diseases. We aim at developing gene therapy for these neurodegenerative diseases, based on correction of patient’s hematopoietic stem cells (HSC) that are isolated from the blood. These HSC are treated in the laboratory with a gene therapy vector to introduce a normal GRN gene. After reinfusion into the patients’ blood, gene-corrected HSC engraft the bone marrow and provide a continuous source of blood and immune cells derived from them, including microglia(-like) cells that can migrate to the brain and normalise PGRN production. Upon proof-of-concept in preclincial models this approach shall be translated in a first-in-man clinical trial at UZH/UMZH.