Tuesday, February 4, 2025
2/4/2025
Project Summary Progranulin is a lysosomal and secreted protein that contains multiple cysteine-rich granulin domains. Although its precise molecular function remains unknown, heterozygous progranulin (GRN) mutations are causal for frontotemporal dementia (FTD). FTD is a devastating disease with a mean survival of 7 years from diagnosis and no approved disease-modifying treatment. Since this is a condition of haploinsufficiency, strategies aimed at increasing progranulin levels are feasible therapeutic approaches. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological disorders. ASOs are short, single-stranded sequences of RNA that are designed to bind to their target RNAs and enable highly specific modulation of target levels. We have developed a novel strategy for increasing progranulin levels by using ASOs to sterically block microRNA binding sites in the human GRN mRNA. We have identified ASOs that effectively increase progranulin protein levels in the brains of humanized GRN mice. Building on this, we will: 1) test if ASO treatment improves FTD-associated behavioral deficits and neuroinflammation in humanized GRN mice with haploinsufficiency, 2) define the timing window for effective ASO treatment, and 3) assess potential off-target effects for lead ASOs. Completion of these studies will generate important preclinical data that provide insights into the utility of this ASO-based therapeutic approach for progranulin-deficient FTD.
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