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Disease-Modifying Genes in Huntington's Disease

Award Number: R01NS091161
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: 04/01/2015
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Disease-Modifying Genes in Huntington's Disease - Huntington’s disease (HD) is a devastating neurodegenerative disorder with a long, costly, debilitating course involving progressive characteristic chorea, psychiatric disturbances, intellectual decline, and a gradual loss of independence, leading to premature death, ~15 years after clinical diagnosis. The lack of any treatment to block or delay HD’s inevitable progression creates a dire need for effective therapies to alleviate the suffering and cost to the individual, family and society. The HD mutation, in the coding sequence of HTT (huntingtin), is an expanded CAG trinucleotide repeat whose length, not the encoded polyglutamine, is the main determinant of the age at clinical onset and other disease landmarks. We have identified 13 genetic modifier loci, many with multiple distinguishable effects, that hasten or delay these clinical landmarks. Seven modifiers are known to be involved in DNA repair and have been implicated in instability of the HTT CAG repeat, arguing that somatic expansion drives the timing of HD pathogenesis, triggering toxicity only after a threshold repeat length is reached. The remaining six modifiers are not tied directly to DNA repair but could influence HD through an indirect effect on somatic expansion or via another mechanism. Investigations of HD postmortem brain strongly support this sequential model of pathogenesis, with recent studies suggesting multiple points at which genetic modifiers could act. In this renewal, we will use human genetics across three aims to more fully examine HD pathogenesis, identifying additional modifiers and delineating their actions to further deepen our understanding of HD pathogenesis, increase the potential for effective disease-modifying treatments, and inform the trials to test them. Genome-wide genetic analyses with a sample size of >26,500 will identify modifiers and their effects using ages at landmarks across the HD trajectory, rates of disease progression at landmarks, imaging measures and other phenotypes, and CAG expansion in blood DNA, along with burden analyses in phenotypically extreme HD individuals. Studies in cell models and derived neuronal cells will classify modifiers by their effects on CAG repeat expansion. Those modifiers that do not affect somatic expansion will be investigated by transcriptomics and CAG sizing in single cells of postmortem HD brain and in cultured striatal medium spiny neurons for effects on toxicity. As our past grant period has demonstrated, the identification of targets implicated by natural variation in biological processes ongoing in patients can provide clues to developing and testing pharmaceutical interventions that push those processes toward a strong therapeutic benefit for HD, with implications for many other DNA repeat diseases. Thus, the promise of this grant, in examining the full HD trajectory with a much larger, well- characterized dataset, continues to be a powerful human genetics-driven route to fulfilling the greatest need of both premanifest and manifest HD patients and their families: effective treatments to block or delay onset and progression of the disease.


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 = $665,255 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	3/19/2026	COMPETING CONTINUATION	$665,255
														Subtotal = $665,255

Issue Date FY: 2024 ( Subtotal = $669,847 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	3/21/2024	NON-COMPETING CONTINUATION	$621,510
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	4/8/2024	NON-COMPETING CONTINUATION	$48,337
														Subtotal = $669,847

Issue Date FY: 2023 ( Subtotal = $690,602 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	6/8/2023	NON-COMPETING CONTINUATION	$690,602
														Subtotal = $690,602

Issue Date FY: 2022 ( Subtotal = $690,661 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/27/2022	NON-COMPETING CONTINUATION	$690,661
2022	2019	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	9/26/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $690,661

Issue Date FY: 2021 ( Subtotal = $689,956 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/1/2021	NON-COMPETING CONTINUATION	$689,956
														Subtotal = $689,956

Issue Date FY: 2020 ( Subtotal = $707,554 )
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	9/26/2020	COMPETING CONTINUATION	$567,585
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/31/2020	COMPETING CONTINUATION	$707,554
2020	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/25/2020	NON-COMPETING CONTINUATION	$0
2020	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	9/26/2020	NON-COMPETING CONTINUATION	-$567,585
														Subtotal = $707,554

Issue Date FY: 2019 ( Subtotal = $610,163 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/8/2019	NON-COMPETING CONTINUATION	$610,163
														Subtotal = $610,163

Issue Date FY: 2018 ( Subtotal = $610,163 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/30/2018	NON-COMPETING CONTINUATION	$61,017
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/20/2018	NON-COMPETING CONTINUATION	$549,146
														Subtotal = $610,163

Issue Date FY: 2017 ( Subtotal = $610,163 )
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/3/2017	NON-COMPETING CONTINUATION	$549,146
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	6/5/2017	NON-COMPETING CONTINUATION	$61,017
														Subtotal = $610,163

Issue Date FY: 2016 ( Subtotal = $610,163 )
2016	2016	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/12/2016	NON-COMPETING CONTINUATION	$610,163
														Subtotal = $610,163

Issue Date FY: 2015 ( Subtotal = $618,776 )
2015	2015	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/12/2015	NEW	$618,776
														Subtotal = $618,776

Grand Total All Awards = $7,173,303

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Disease-Modifying Genes in Huntington's Disease

Award Number: R01NS091161

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: 04/01/2015

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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