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Targeted progranulin therapy for TDP-43 Proteinopathy

Award Number: R56AG097867
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Targeted progranulin therapy for TDP-43 Proteinopathy - Project Summary/Abstract. TDP-43 proteinopathy is the primary pathology of ALS and ~45% of frontotemporal dementia (FTD-TDP), and is a common co-pathology of Alzheimer’s disease. TDP-43 proteinopathy is associated with neuronal loss and clinical decline in these diseases, and currently has no disease-modifying therapies. Genetic data reveal a relationship between TDP-43 proteinopathy and low levels of progranulin, though the mechanism underlying this relationship is still unclear. Progranulin (GRN) mutations, which typically cause progranulin haploinsufficiency, cause FTD-TDP, so progranulin-boosting therapies have entered clinical trials for people with GRN mutations. Boosting progranulin levels is also neuroprotective in wild-type neurons, and progranulin overexpression reduces neuronal dysfunction after TDP-43 overexpression or knockdown. Though it is unclear if these protective effects are due to regulation of TDP-43, these data raise the possibility that progranulin-boosting therapies may be useful for treating sporadic TDP-43 proteinopathy. This could have a significant therapeutic impact, but sustained elevation of progranulin may have several adverse side effects. Understanding the mechanism of progranulin’s protective effects will thus be critical for optimizing the efficacy and safety of these therapies. Progranulin is a pro-protein that may act through multiple molecular targets, so we have investigated targeted progranulin delivery as a way to optimize progranulin-boosting therapy. Progranulin is constitutively secreted and engages in extracellular signaling before being trafficked to lysosomes, where it facilitates hydrolase activity. It is not clear which of these actions mediates progranulin’s protective effects. To distinguish these mechanisms, we adopted a molecular targeting strategy to deliver progranulin to lysosomes without secretion (L-PGRN). Based on preliminary data, we propose to test the hypothesis that delivering progranulin to neuronal lysosomes will protect against TDP-43 proteinopathy. In Aim 1 we will use novel L-PGRN knock-in mice, in which progranulin maintains lysosomal function but is not secreted, to test the hypothesis that progranulin’s actions in lysosomes are sufficient to prevent the TDP-43 dysregulation observed in progranulin-insufficient mice. In aim 2, we will use progranulin (PGRN) or L-PGRN viral vectors in primary cortical and iPSC-derived neurons to test the hypothesis that boosting progranulin will reduce TDP-43 mislocalization from the nucleus and/or promote clearance of cytoplasmic TDP-43. We will also determine if any protective effects are dependent on autophagy or the critical protease cathepsin D. In aim 3 we will test whether AAV-PGRN or L-PGRN protect against TDP-43 dysregulation and neuronal dysfunction in TDP-43 mutant iPSC- derived neurons and two TDP-43 mouse lines. These studies will provide comprehensive preclinical data on progranulin-boosting therapy for TDP-43 proteinopathy, and determine the key cellular compartment for progranulin delivery. This could have immediate impact by guiding choice of therapies that preferentially increase extracellular or intracellular progranulin.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $486,779 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	8/25/2026	NEW	$486,779
														Subtotal = $486,779

Grand Total All Awards = $486,779

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Targeted progranulin therapy for TDP-43 Proteinopathy

Award Number: R56AG097867

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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