Restoration of progranulin by engineered hematopoietic stem cell–derived microglia corrects phenotypes of granulin knockout mice

Autologous hematopoietic stem/progenitor cell (HSC)–gene therapy (GT) represents a promising therapeutic option for progranulin (PGRN)–related neurodegenerative diseases due to mutations in the PGRN encoding gene ( GRN ), such as frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis 11 (CLN11). These conditions are characterized by a deficiency in PGRN, have no cure, and represent an unmet medical need. We report on the efficacy and feasibility of an HSC GT approach that used a lentiviral vector encoding the human GRN complementary DNA to transduce HSCs that then were transplanted into a Grn −/− mouse model, which mirrors both FTD and CLN11 phenotypes. Two promoters, one with medium-low strength (…

• OT
  Orchard Therapeutics