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Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia

Award Number: R43NS134421
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: 09/01/2023
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia - Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia Abstract Frontotemporal dementias (FTD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative diseases. A hexanucleotide repeat expansion in C9orf72 accounts for >10% of all cases. Non-AUG dependent translation of expanded repeats results in accumulation of several dipeptide repeat (DPR) proteins, of which poly-GA appears central to the pathology of C9orf72 disease. Aggregation of poly-GA inhibits the proteasome and leads to TDP-43 aggregation. Despite widespread poly-GA expression in C9orf72 mouse models, specific disease-relevant neuron populations are especially sensitive to poly-GA toxicity. Antisense oligonucleotides directed to C9orf72 are effective in mice, as is a dominant negative protein kinase R (PKR) that attenuates poly-GA accumulation. Preliminary data indicate that active vaccination induces high antibody titers and nearly complete prevention of motor deficits and microglia activation in mice, suggesting poly-GA as a feasible target to treat C9orf72 FTD/ALS. Poly-GA antibodies block aggregation and spreading of poly-GA and attenuate downstream TDP-43 pathology in vitro, and improve motor and behavioral deficits in mouse models. These data suggest that immunotherapy is currently the best approach to reduce toxicity of aggregates that are found even in pre-symptomatic carriers. Our team has identified potent murine antibodies that demonstrate activity in a C9orf72 mouse model. During this Phase 1 study, we propose to humanize our lead anti-GA antibody and conduct preclinical validation of anti-GA antibody therapy in several disease-relevant mouse models.


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: 2025 ( Subtotal = $0 )
2025	2023	PANORAMA RESEARCH INCORPORATED	1230 BORDEAUX DR	SUNNYVALE	CA	94089	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/16/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $299,989 )
2023	2023	PANORAMA RESEARCH INCORPORATED	1230 BORDEAUX DR	SUNNYVALE	CA	94089	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/11/2023	NEW	$299,989
														Subtotal = $299,989

Grand Total All Awards = $299,989

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Targeted immunotherapy for amyotrophic lateral sclerosis and frontotemporal dementia

Award Number: R43NS134421

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: 09/01/2023

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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