Localized chelation therapy for removing calcification in pad
Active Project Grant Awarded Last action
- Award ID
- R01HL180371
- Recipient
-
University Of Nebraska UEI FZRNFQTKADH1
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $1,342,690
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 31% complete
- Place of performance
- Omaha, NE 68182, USA
Award details come from USAspending.gov.
Description
- Abstract
- Peripheral artery disease (pad) leads to high morbidity, mortality, and diminished life quality, with arterial calcification substantially increasing the risk of treatment failure and quadrupling the likelihood of amputation. Currently, there are no effective ways of removing arterial calcification. One potential therapy involves disodium ethylenediaminetetraacetic acid (EDTA), a chelating agent, but its systemic use in doses high enough to be effective in the vasculature causes severe side effects. We propose a novel method of delivering EDTA directly to calcified lesions using a microneedle catheter and hypothesize that local EDTA chelation removes arterial calcium, reduces inflammation, and improves limb flexion hemodynamics while avoiding systemic side effects. To test this hypothesis, we will leverage our expertise in evaluating over 1,000 human lower extremity arteries with various types of calcification, and our novel preclinical large animal model that recapitulates arterial calcification observed in human vessels. This will be achieved through two aims. First, we will use our unique biobank of calcified human fpas from tissue donors and amputated lower extremity arteries to develop a local EDTA chelation strategy to reduce or resolve calcific lesions in a burden, time, and dose-dependent manner. We will use donor tissues to assess EDTA delivery location, distribution, tissue integrity, and drug kinetics, and employ live calcified amputated human specimens and healthy animal explants to test therapeutic EDTA levels, measuring myogenic tone, metabolic activity, cellularity/confluency, and endothelial function in biomimetic culture. Second, we will employ our novel swine model of peripheral artery calcification to determine the safety and effectiveness of local EDTA treatment. Bilateral femoral artery calcification will be induced in ossabaw swine on an atherogenic diet using an intravascular CACL2 injection delivered via a microneedle catheter. Imaging will assess baseline arterial pulsatility, and measurements in straight and bent limbs will assess the influence of calcification on arterial biomechanics and flow as a result of limb flexion. Calcific lesions will then be treated with locally-delivered EDTA tuned to a specific calcium burden, while the contralateral calcified artery will serve as a control. Monthly imaging will assess changes in pulsatility, bone density, arterial calcium levels, and hemodynamics in various limb positions. After sacrifice, ΜCT will determine the extent and pattern of calcification, mechanical tests will evaluate arterial compliance, and histological and immunohistochemical analyses of arteries and kidneys will assess cellular and matrix structure, repair, and toxicity. Our large animal model accurately replicates the primary characteristics of peripheral artery calcification, enabling the use of human- sized devices within a rigorously controlled environment. By integrating IT with a unique collection of calcified human arteries from our laboratory, we aim to develop localized strategies for the safe and effective removal of arterial calcium, improving clinical outcomes for patients with pad. This novel approach is set to transform clinical practices by offering a viable treatment for a condition that currently lacks effective therapeutic options.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $652,762 | |
| Original award | $689,928 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Board Of Regents Of The University Of Nebraska | $89,181 | |
| Virginia Polytechnic Institute & State University | $129,580 | |
| Board Of Regents Of The University Of Nebraska | $29,557 | |
| Board Of Regents Of The University Of Nebraska | $79,643 | |
| Virginia Polytechnic Institute & State University | $132,120 |
Quick answers
Who received award R01HL180371?
R01HL180371 was awarded to University Of Nebraska by National Heart Lung and Blood Institute (National Institutes of Health) on September 5, 2025.
How much is award R01HL180371 worth?
$1,342,690 has been obligated on R01HL180371.
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