What about a human model system? To assess this we also created a novel human TMEM106B/GRN DKO iPSC model that recapitulates TDP-43 pathology, neurodegeneration and lysosomal abnormalities – all phenotypes can be rescued by treatment with PTV:PGRN (7/8)

Increased PGRN levels lead to a reduction of TDP-43 pathology, decreased neurodegeneration and an amelioration of motor deficits and behavioural phenotypes! (6/8)

Applying AAV(L):bPGRN to Tmem106b x Grn double KO mice, we show that a single injection can restore progranulin levels in neurons, microglia, astrocytes and endothelial cells for a prolonged time (5/8)

In this study, we use a novel therapeutic approach, combining protein replacement with gene therapy. We exploit a liver-transducible AAV (AAV(L)), which induces brain penetrant (b)PGRN expression in hepatocytes and releases it to the blood to be transcytosed into the brain (4/8)

To get around this our collaborators at Denali Therapeutics have recently designed a novel protein replacement approach in the form of a brain penetrant version of PGRN that shuttles through the BBB via transferrin receptor-mediated transcytosis (3/8)