Thursday, January 1, 2026 1/1/2026

PET Imaging of Vaso-Occlussive Crisis in Sickle Cell Disease

Award Number: R01HL154629
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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PET Imaging of Vaso-Occlussive Crisis in Sickle Cell Disease - Project Summary/Abstract Sickle cell disease (SCD) is a genetic disorder that affects millions worldwide. Research in transgenic SCD mice has shown that SCD is characterized by the overexpression of adhesion molecules (hyperadhesion) on the endothelium and blood cells. Hyperadhesion causes vascular occlusion, which in turn leads to the hallmark acute pain episodes of SCD named vaso-occlusive crises (VOC). Key players in hyperadhesion and VOC are the adhesion molecules P-selectin, that tethers reticulocytes and neutrophils to the endothelium, and Very Late Antigen-4 (VLA-4), that is responsible for firm adhesion downstream of P-selectin. The central challenge in the clinical management of SCD is that there exist no biomarkers nor direct visualization of hyperadhesion in humans. The knowledge deficit on hyperadhesion is consequential, as new drugs targeting adhesion molecules to prevent VOC are being developed, yet there are no biomarkers to guide their use. Specifically, SCD care providers cannot adopt a precision medicine approach to select which patients will respond to the P-selectin blocker crizanlizumab, which is only efficacious in ~50% of patients, carries a high cost, and may cause severe adverse reactions. This proposal aims to advance the field by developing the first-ever biomarker to image hyperadhesion in humans with SCD by imaging activated VLA-4. We hypothesize that positron emission tomography (PET) imaging of VLA-4 will measure hyperadhesion before treatment, and its decrease in response to anti-hyperadhesive drugs. Our multidisciplinary team has developed the PET tracer 64Cu-CB-TE1A1P-PEG4- LLP2A (64Cu-LLP2A) that binds to activated VLA-4. We found that LLP2A can detect VLA-4-mediated hyperadhesion in response to lipopolysaccharide (LPS) in SCD mice, and that hyperadhesion is reduced by treatment with anti-P-selectin mAb (analogous to crizanlizumab). We now propose to i) elucidate the role of additional triggers of hyperadhesion (i.e. hemin and hypoxia) in mice, to more thoroughly model human pathology (Aim 1); ii) to compare 64Cu-LLP2A uptake in mice after P-selectin blockade vs. voxelotor, a new FDA-approved drug for SCD that targets hemolysis and may impact hyperadhesion indirectly (Aim 2); and iii) to image patients with SCD using 64Cu-LLP2A, for which we were granted regulatory approval in 2020, before and after treatment with crizanlizumab (Aim 3). Our studies, if successful, will pave the way for biomarker-driven precision medicine and future research for this underserved group of patients. Future clinical trials of anti-VOC treatments may incorporate 64Cu-LLP2A to predict, quantify, and monitor response.


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 = $0 )
2026	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	4	12/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $554,636 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	4	3/25/2025	NON-COMPETING CONTINUATION	$499,174
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	001	4	7/29/2025	NON-COMPETING CONTINUATION	$55,462
														Subtotal = $554,636

Issue Date FY: 2024 ( Subtotal = $694,482 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	3	6/21/2024	NON-COMPETING CONTINUATION	$694,482
														Subtotal = $694,482

Issue Date FY: 2023 ( Subtotal = $666,750 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	2	5/23/2023	NON-COMPETING CONTINUATION	$666,750
														Subtotal = $666,750

Issue Date FY: 2022 ( Subtotal = $763,136 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Blood Diseases and Resources Research	000	1	3/11/2022	NEW	$763,136
														Subtotal = $763,136

Grand Total All Awards = $2,679,004

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PET Imaging of Vaso-Occlussive Crisis in Sickle Cell Disease

Award Number: R01HL154629

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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