# PET Imaging of Vaso-Occlussive Crisis in Sickle Cell Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $763,136

## Abstract

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.

## Key facts

- **NIH application ID:** 10366801
- **Project number:** 1R01HL154629-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Carolyn J. Anderson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $763,136
- **Award type:** 1
- **Project period:** 2022-03-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10366801

## Citation

> US National Institutes of Health, RePORTER application 10366801, PET Imaging of Vaso-Occlussive Crisis in Sickle Cell Disease (1R01HL154629-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10366801. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*