Moderator of 1 Session
Presenter of 1 Presentation
RESCUE OF A LYSOSOMAL STORAGE DISORDER CAUSED BY GRN LOSS-OF-FUNCTION WITH A BRAIN PENETRANT PROGRANULIN BIOLOGIC
Abstract
Aims
GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function.
Methods
We utilized targeted lipidomic profiling to characterize changes in lysosomal lipids in the brain of Grn-/- mouse as well as in GRN-FTD patient CSF and plasma samples. Further, we investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN—a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution.
Results
Here, we found that Grn–/– mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn–/– brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. PTV:PGRN rescued various Grn–/– phenotypes in primary murine macrophages and hu- man iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn–/– CNS, including microgliosis, lipofuscinosis, and neuronal damage.
Conclusions
PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.