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Validating Secretory Autophagy as a Therapeutic Strategy for Diverse Forms of ALS and FTD

Award Number: R01NS097850
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Validating Secretory Autophagy as a Therapeutic Strategy for Diverse Forms of ALS and FTD - ALS, FTD, and Alzheimer’s are complex diseases that each result from many diverse genetic etiologies. Although therapeutic strategies that target specific causal mutations (e.g. SOD1 ASOs) may prove effective against individual forms of ALS and FTD, these approaches cannot address the vast majority of cases that have unknown genetic etiology. Moreover, given the large number of different genes that likely contribute to ALS and FTD and the fact that each genetic form is relatively rare, this strategy may be difficult to implement for all cases. Thus, there is a pressing need for new therapeutic strategies that rescue multiple forms of ALS and FTD, particularly those with unknown genetic etiologies. To identify new therapeutic targets that rescue multiple forms of ALS, we performed unbiased chemical screens to search for targets that can rescue the degeneration of iPSC motor neurons from multiple C9ORF72 and sporadic ALS patients. Inhibitors of PIKFYVE kinase were among the most potent and broadly-efficacious compounds across patient lines. Surprisingly, the data show that PIKFYVE inhibition rescues neurodegeneration by blocking autophagosome- lysosome fusion, which induces secretory autophagy to clear misfolded proteins including C9ORF72 dipeptide repeat proteins and TDP-43 through exosomal secretion. The accumulation of misfolded proteins can induce neuron death and is a common feature of neurodegenerative diseases. Although studies have sought to stimulate known proteostasis pathways including the proteosome and autophagy, these pathways decline during aging and may be difficult to rescue effectively. Intriguingly, recent studies have shown that neurons use exosomal secretion as a third proteostasis pathway. However, it remains unknown if this pathway can be harnessed to treat ALS and related neurodegenerative diseases. The central hypothesis of the proposed study that secretory autophagy is one of the most potent ways to prevent neurodegeneration in ALS, FTD, and Alzheimer’s disease differs from mainstream thinking in the field. Evaluating this hypothesis is crucial because activating the proteasome and autophagy has had mixed results in neurodegeneration models. The proposed study will 1) confirm that secretory autophagy is the therapeutic mechanism of PIKFYVE inhibition, 2) determine the efficacy of secretory autophagy in ALS, FTD, and Alzheimer’s disease patient-derived neurons, and 3) validate the efficacy of PIKFYVE suppression with antisense oligonucleotides in vivo. This application seeks to shift current research by validating the induction of secretory autophagy as a highly effective therapeutic strategy for diverse forms of ALS, FTD, and Alzheimer’s disease. The proposed study will establish PIKFYVE suppression and secretory autophagy as critical therapeutic targets for ALS and related neurodegenerative diseases. More broadly, this therapeutic strategy may be effective for other diseases driven by aberrant protein accumulation.


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: 2024 ( Subtotal = $686,752 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/5/2024	NON-COMPETING CONTINUATION	$686,752
														Subtotal = $686,752

Issue Date FY: 2023 ( Subtotal = $686,752 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	7/3/2023	NON-COMPETING CONTINUATION	$686,752
2023	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/26/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $686,752

Issue Date FY: 2022 ( Subtotal = $620,824 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	6/16/2022	NON-COMPETING CONTINUATION	$620,824
														Subtotal = $620,824

Issue Date FY: 2021 ( Subtotal = $720,508 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	5	6/18/2021	SUPPLEMENT FOR EXPANSION	-$54,209
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	009	6	9/21/2021	NON-COMPETING CONTINUATION	-$151,495
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/21/2021	SUPPLEMENT FOR EXPANSION	$79,217
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/2/2021	SUPPLEMENT FOR EXPANSION	$72,278
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	5/21/2021	NON-COMPETING CONTINUATION	$774,717
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	5	6/23/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	008	5	9/12/2021	COMPETING CONTINUATION	$56
2021	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	5	5/23/2021	COMPETING CONTINUATION	$60,113
2021	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	5/23/2021	NON-COMPETING CONTINUATION	-$60,113
2021	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	007	4	9/12/2021	NON-COMPETING CONTINUATION	-$56
														Subtotal = $720,508

Issue Date FY: 2020 ( Subtotal = $674,414 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	7/13/2020	COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	5	9/18/2020	COMPETING CONTINUATION	$32,611
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	7/7/2020	COMPETING CONTINUATION	$641,803
2020	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/3/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $674,414

Issue Date FY: 2019 ( Subtotal = $431,727 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	8/26/2019	NON-COMPETING CONTINUATION	$431,727
2019	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/5/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $431,727

Issue Date FY: 2018 ( Subtotal = $596,470 )
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	9/17/2018	NON-COMPETING CONTINUATION	$596,470
														Subtotal = $596,470

Issue Date FY: 2017 ( Subtotal = $654,725 )
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/18/2017	SUPPLEMENT FOR EXPANSION	$39,461
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	2	8/25/2017	NON-COMPETING CONTINUATION	-$7,503
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	4/27/2017	SUPPLEMENT FOR EXPANSION	$5,886
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	7/11/2017	SUPPLEMENT FOR EXPANSION	$12,908
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	8/16/2017	NON-COMPETING CONTINUATION	$603,973
														Subtotal = $654,725

Issue Date FY: 2016 ( Subtotal = $412,500 )
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/23/2016	NEW	$0
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/24/2016	NEW	$360,938
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	9/26/2016	NEW	$51,562
														Subtotal = $412,500

Grand Total All Awards = $5,484,672

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Validating Secretory Autophagy as a Therapeutic Strategy for Diverse Forms of ALS and FTD

Award Number: R01NS097850

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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