Denali Therapeutics Inc. announced publication of preclinical proof of concept for using its Protein Transport Vehicle (PTV) to enhance brain uptake of peripherally administered progranulin (PTV:PGRN). This approach may have utility in treating certain types of frontotemporal dementia (FTD), especially FTD-GRN caused by progranulin deficiency. The preclinical research showed that progranulin replacement therapy with Denali’s PTV:PGRN rescued both neurodegeneration and microglial dysfunction in progranulin-deficient mice. The research also provides new insight into the molecular and cellular mechanisms that may contribute to FTD, identifying novel roles of progranulin in lysosomal function and lipid metabolism, as well as lysosome biomarkers with potential clinical utility. PTV:PGRN is engineered to bind transferrin receptor molecules, which are present in large amounts on endothelial cells of the BBB and normally function to transport iron into the brain. This approach enables PTV:PGRN to be actively transported into the brain, potentially overcoming a long-standing challenge to the field of delivering protein therapeutics across the BBB. New insights on the role of progranulin and effects of PTV:PGRN in preclinical models of FTD: Mutations in the GRN gene, which encodes the progranulin protein, generally result in reduced protein levels of progranulin and are amongst the most common genetic causes of FTD. The studies published in Cell used two common models of FTD-GRN, genetically engineered progranulin-deficient mice as well as iPSC-derived human microglial cells, to investigate the role of progranulin and effects of PTV:PGRN treatment on disease pathology. The preclinical research showed that lysosomes – which function as the “digestive system” of cells – are the primary cellular organelles impacted by progranulin deficiency. A new finding revealed in the preclinical studies was that progranulin regulates lysosomal function through binding to and stabilizing a lysosome-specific lipid, bis(monoacylglycero)phosphate (BMP), which is critical for normal lysosomal function. In the progranulin-deficient mice, BMP lipid levels were profoundly decreased, which resulted in reduced activity of the lipid-metabolizing enzyme glucocerebrosidase (GCase) and accumulation of the GCase substrate glucosylsphingosine (GlcSph); GCase is known to be involved in Gaucher disease and GBA-linked Parkinson’s disease. A mild decrease in BMP and an increase in GlcSph was also found in biofluid samples from patients with FTD, with or without GRN mutations. Treatment of progranulin-deficient mice or human cells with PTV:PGRN was sufficient to rescue a range of lysosomal defects, including BMP deficiency, GlcSph accumulation, lysosomal vacuolization and lysosomal membrane damage. In addition, PTV:PGRN corrected lipofuscinosis, microgliosis and astrogliosis, which are common disease-relevant brain pathologies in progranulin-deficient mice that are also present in patients with FTD-GRN.