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Augmenting Lysosomal Proteases as a Therapeutic Strategy to Mitigate TDP-43 Pathology in ALS and FTD

Award Number: R01NS146307
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Augmenting Lysosomal Proteases as a Therapeutic Strategy to Mitigate TDP-43 Pathology in ALS and FTD - PROJECT SUMMARY/ABSTRACT Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders with no broadly effective disease-modifying therapies. A central pathology in both diseases is the mislocalization and aggregation of the RNA-binding protein TDP-43, which occurs in ~97% of ALS and ~50% of FTD cases. Recent work implicates lysosomal dysfunction in promoting TDP-43 pathology, highlighting the importance of endogenous proteases (including cathepsin B, cathepsin D, and asparaginyl endopeptidase) in TDP-43 clearance. This proposal aims to define the therapeutic potential of enhancing these lysosomal proteases in restoring TDP-43 homeostasis and improving neuronal health in ALS/FTD. To test this strategy, we will employ a multi-faceted approach that combines human induced pluripotent stem cell (iPSC) technology, CRISPR-mediated gene modulation, and disease-relevant neuronal and organoid models. Aim 1 will determine the therapeutic effects of augmenting cathepsin B, cathepsin D, and asparaginyl endopeptidase expression on TDP-43 proteostasis and neuronal viability in iPSC-derived cortical and motor neurons. More specifically, we will use CRISPR-activation (CRISPRa) to enhance protease levels and assess the impact of this protease augmentation on TDP-43 clearance, TDP-43 pathology, neuronal morphology, and viability. We will also employ CRISPR-interference (CRISPRi) and non-targeting constructs as key controls. Aim 2 will extend these studies to 3D brain organoids containing iPSC-derived neurons and astrocytes. This will allow us to dissect neuron-autonomous versus neuron non-autonomous mechanisms of TDP-43 clearance, elucidating the potential contributions of glial cells. Aim 3 will employ a comprehensive multiomics approach, including RNA-sequencing and proteomics to define the molecular changes associated with protease augmentation. By integrating these approaches, we will determine whether enhancing lysosomal protease activity is a viable therapeutic strategy for ALS and FTD. This work will establish whether neuron-intrinsic or astrocyte-supported mechanisms are primarily responsible for TDP-43 clearance, providing critical insights into the cellular processes involved. Furthermore, the multiomics data will identify novel downstream effectors and pathways that could serve as additional therapeutic targets. The successful completion of this project will lay the foundation for the development of innovative treatments targeting TDP-43 proteostasis, with the ultimate goal of improving outcomes for patients suffering from these devastating neurodegenerative diseases.


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 = $540,649 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/15/2026	NEW	$540,649
														Subtotal = $540,649

Grand Total All Awards = $540,649

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Augmenting Lysosomal Proteases as a Therapeutic Strategy to Mitigate TDP-43 Pathology in ALS and FTD

Award Number: R01NS146307

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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