Progranulin is a lysosomal and secreted protein that contains multiple cysteine-rich granulin domains; its precise molecular function remains unknown. Progranulin (GRN) mutations are causal for frontotemporal dementia (FTD), which is a devastating disease with a mean survival of 3.8 years from diagnosis and no cure currently available. Since progranulin-deficient FTD is a disease of haploinsufficiency, strategies aimed at increasing progranulin levels are feasible therapeutic approaches. We recently generated a knock-in mouse model of FTD harboring the common patient nonsense mutation GRNR493X, and we established that the nonsense-mediated mRNA decay (NMD) pathway contributes to the markedly reduced mutant progranulin mRNA levels in this mouse model, as wel`l as in patient-derived fibroblasts containing the GRNR493X mutation. Moreover, our cell-based studies indicate that the progranulin R493X mutant protein is functional when re- expressed in progranulin-deficient cells. Based on these results, we hypothesize that inhibiting NMD-mediated degradation of the mutant GrnR493X mRNA would increase functional progranulin levels and thereby improve FTD-associated behavioral changes and neuropathology. We will test this hypothesis in the following two specific aims:
Aim 1) Test in vivo efficacy of ASOs that block NMD-mediated degradation in the GrnR493X knock-in mouse model of FTD, and Aim 2) Design and test ASOs that target NMD-mediated degradation of the human GRNR493X mRNA. Completion of these studies will generate important preclinical data that provide insights into the utility of ASO-based NMD inhibition as a therapeutic approach for progranulin-deficient FTD.
Progranulin mutations cause frontotemporal dementia (FTD), a devastating disease for which no cure currently exists. In this project, we will test a novel therapeutic approach for treating progranulin-deficient FTD that uses antisense oligonucleotides (ASOs) to restore normal progranulin levels in cellular and mouse models. Completion of these studies will generate important preclinical data that provide insights into the utility of this approach as a potential therapy for progranulin-deficient FTD.