SRP492637 PRJNA1082327 GSE260606 Gene expression profile of brain tissue from wildtype and GRN knock-out mice treated with an AAV driving expression of PTV-Progranulin in the liver PGRN is involved in lysosomal function and is expressed in the brain. Grn knock-out (KO) mice develop several pathologies including lysosomal lipi accumulation, gliosis and neurodegeneration. Here we seek to determine if we can rescue Grn KO pathologies with a peripherally delivered AAV, that targets the liver, and drives expression of full length PGRN fused to a mouse TfR binding scFv (AAV(L):bPGRN. The PGRN fusion protein expressed by this AAV (8D3:PGRN), is brain penetrant. To study this, Grn KO mice were given a single IV injection of either saline or AAV(L):bPGRN at 4 months of age. After 8 months when the mice were 12 months of age, brain samples were collected and bulk RNA sequencing was performed to assess correction of transcriptional changes. Grn wild type (WT) mice treated with saline were also included as a control. Overall design: We generated AAV(L):bPGRN (L = liver, b = brain-penetrant), a liver-targeting adenovirus (AAV) encoding a fusion protein (8D3:PGRN) consisting of a single chain fragment variable (scFv) antibody recognizing mouse TfR (transferrin receptor) fused to human PGRN (hPGRN). Grn knockout (KO) mice were treated with either an AAV driving expression of 8D3-linked progranulin (AAV(L)-8D3-PGRN) in the liver (n=5) or saline (n=5). As a control, wildtype (WT) animals treated with saline (n=6) were included. GSE260606 pubmed 38838131