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Safety and modulation of ABCC9 pathways by nicorandil for the treatment of hippocampal sclerosis of aging (SMArT???HS)

Award Number: R01AG061111
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract The proposed project is a pilot clinical trial investigating a potential treatment for hippocampal sclerosis of aging (HS-Aging). A major subtype of “Alzheimer's disease and related dementia” (ADRD), HS-Aging affects 10-25% of all elderly individuals. HS-Aging is typically misdiagnosed as Probable AD or AD-type dementia in the clinical setting. Unfortunately, there currently is no validated biomarker to diagnose HS-Aging during life, and there is no known therapy. We will test the safety and efficacy of nicorandil for HS-Aging, based on our prior work elucidating a pharmacologically targetable mechanism underlying the disease. Nicorandil is a vasorelaxant drug, used clinically to treat chronic heart failure in the elderly population. Pharmacologically, Nicorandil is an agonist for a protein (SUR2) that is encoded by a gene that we found to be linked to HS-Aging risk. Primary specific aims follow: Specific Aim #1: Evaluate safety and neurodegenerative biomarkers linked to HS-Aging pathology in nicorandil vs. placebo treated subjects by: a. Conducting a double-blind, randomized, placebo-controlled, clinical trial of nicorandil in 62 participants (both sexes, >75 years old, CDR 0.5 or 1, with HS-Aging profile in CSF and MRI biomarkers [amyloid and phospho-tau negative, with evidence for hippocampal atrophy; A-/T-/N+]) over a 96-week treatment period; b. Evaluating the safety of nicorandil administration in the elderly at risk for HS-aging (this is the primary outcome measure) that will inform future trial design; and, c. Measuring structural MRI (3D-T1; hippocampal atrophy is the main efficacy outcome measure), cognitive tests, and CSF levels of nicorandil, tau, phospho-tau, and Aß(1-42) at baseline and week 96. Specific Aim #2: Optimize and further explore HS-Aging biomarkers by: a. Refining MR imaging analysis (including hippocampal volumetric assays, arterial spin labeling (ASL), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS) techniques that may distinguish participants with probable HS-Aging from those with positive AD biomarkers; b. Performing proteomic discovery analysis in CSF to identify and evaluate potential HS-Aging biomarkers to complement the A/T/N framework utilizing our prospective cohort with Aß(1-42), phospho-tau, and neurodegeneration markers and MR imaging as a control cohort for AD. This specific aim will directly test and enhance the clinical utility of the A/T/N framework for diagnosis of degenerative disease state; and, c. Following our published and replicated neurocognitive testing marker that is associated with HS-Aging pathology, we will optimize the clinical and neurocognitive criteria for disease diagnosis based on the prospects of a relatively long-running (96 week) early-phase clinical trial.


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 = $633,155 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	4	2/21/2024	NON-COMPETING CONTINUATION	$633,155
														Subtotal = $633,155

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	3	3/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $716,551 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	3	4/21/2022	NON-COMPETING CONTINUATION	$71,655
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	3	1/6/2022	NON-COMPETING CONTINUATION	$644,896
														Subtotal = $716,551

Issue Date FY: 2021 ( Subtotal = $740,936 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	002	2	2/10/2021	NON-COMPETING CONTINUATION	$74,094
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	2	12/8/2020	NON-COMPETING CONTINUATION	$666,842
2021	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	1	10/27/2020	NEW	$0
														Subtotal = $740,936

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	1	11/11/2019	NEW	$0
2020	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	001	1	11/22/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $763,006 )
2019	2019	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Aging Research	000	1	1/16/2019	NEW	$763,006
														Subtotal = $763,006

Grand Total All Awards = $2,853,648

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Safety and modulation of ABCC9 pathways by nicorandil for the treatment of hippocampal sclerosis of aging (SMArT???HS)

Award Number: R01AG061111

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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