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 (HLA-DRA gene-based promoter regulated by inflammation) and the other with medium-high strength [ubiquitous phosphoglycerate kinase (PGK) promoter], were compared for HSC transduction. Moreover, intravenous and intracerebroventricular HSC administration were compared. Under all tested conditions, a partial reconstitution of PGRN production by microglia-like cells (MLCs) derived from genetically corrected Grn-/- HSCs was observed, which uniformly led to a correction of lipid accumulation, reduced gliosis, and improved social recognition in Grn-/- mice. Therapeutic effects were similarly achieved with either of the promoters and administration routes and particularly also when the PGRN-expressing cells and their MLC progeny had engrafted exclusively in the central nervous system (CNS) after intracerebroventricular transplantation. These findings suggest that a durable yet modest restoration of PGRN expression in the CNS is sufficient to correct pathology.