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Impact of PCSK9 inhibition on abdominal aortic aneurysm pathobiology and growth

Award Number: R01HL166991
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Impact of PCSK9 inhibition on abdominal aortic aneurysm pathobiology and growth - PROJECT SUMMARY / ABSTRACT Abdominal aortic aneurysm (AAA) is a life-threatening condition in which progressive dilatation of the infrarenal aorta leads to rupture. With ~2.3 million prevalent cases in the United States, AAA afflicts ~4% of the population ≥ 65 years of age and is responsible for ~41,000 deaths annually. No medical therapies exist that prevent AAA, AAA growth, rupture, or aneurysm-related death. The only efficacious intervention is surgery. Genome-wide association studies (GWAS) and preliminary pharmacogenetic causal inference studies from AAA GWAS demonstrate that both LDL-C lowering and PCSK9 inhibition are protective of AAA. The greatest therapeutic opportunities for pharmacological treatment of AAA lie in prevention of aneurysm expansion in individuals with small AAA. Despite our team's robust evidence linking LDL-C and PCSK9 to the development of AAA, their causal role in AAA growth remains unknown and the data to support conducting a large-scale efficacy trial is lacking. This project will leverage two orthogonal approaches to generate data that supports the role of LDL-C in AAA growth and that intensive LDL-C lowering with PCSK9 inhibitors will protect against aneurysm expansion. First, we will perform a multi-ancestry meta-analysis of GWAS of AAA growth rate and leverage these data to conduct genetic causal inference experiments interrogating the role of PCSK9 and LDL-c in AAA expansion. Second, we will conduct a quadruple-blind, randomized, placebo-controlled mechanistic clinical trial to test the effect of intensive short-term LDL-C lowering with PCSK9 inhibition on inflammation in the aneurysmal aortic wall; the primary outcome will be the production of the inflammatory cytokine interleukin 6 (IL-6) monocytes/macrophages in the aortic wall as measured by single nucleus RNA sequencing and confirmed by bulk RNA sequencing tissue- based immunofluorescence. Key secondary outcomes include: 1) matrix metalloproteinase 9 (MMP-9) production and activity; 2) relative numbers, cell type distribution, and inflammatory state of infiltrating immune cells; and 3) the relative number and proliferative/contractile state of aortic smooth muscle cells in the aortic wall. Successfully completing the proposed research will establish causal evidence linking LDL-C and AAA growth, and the ability to modulate this with PCSK9 inhibition. It will provide human mechanistic evidence that PCSK9 inhibitors induce anti-inflammatory changes in aneurysmal aortic wall that protect from aneurysm expansion. These data will provide the justification for a future large-scale randomized controlled trial to assess the efficacy of PCSK9 inhibitors to treat AAA.


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 = $675,678 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	3	9/23/2025	NON-COMPETING CONTINUATION	$67,567
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	3	3/28/2025	NON-COMPETING CONTINUATION	$608,111
														Subtotal = $675,678

Issue Date FY: 2024 ( Subtotal = $589,331 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$541,223
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	2	6/14/2024	NON-COMPETING CONTINUATION	$48,108
														Subtotal = $589,331

Issue Date FY: 2023 ( Subtotal = $663,529 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	1/17/2023	NEW	$663,529
														Subtotal = $663,529

Grand Total All Awards = $1,928,538

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Impact of PCSK9 inhibition on abdominal aortic aneurysm pathobiology and growth

Award Number: R01HL166991

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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