Localizing therapeutics to target lung myofibroblasts and reverse fibrosis
Active Project Grant Awarded Last action
- Award ID
- R01HL175948
- Recipient
-
Proteogenomics Research Institute For Systems Medicine UEI EAZXZLPJYJZ2
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,352,399
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date 56% complete
- Place of performance
- La Jolla, CA 92037, USA
Award details come from USAspending.gov.
Description
- Abstract
- Lung diseases are a global public health problem with significant morbidity, inadequate therapies and a very high burden to society. Of these, idiopathic pulmonary fibrosis (IPF) is particularly challenging to treat as existing therapeutics, nintedanib and pirfenidone, only slow progression but do not reverse fibrosis. One of the reasons is in part due to the fact that the vascular endothelium represents a key barrier to effective delivery of anti-fibrotic drugs into lung tissue. Current systemic lung therapies rely on passive transvascular transport to move circulating drugs from the bloodstream and into the target tissue. Hoverer, only minute fractions of the injected doses actually reach the lung tissue, diminishing efficacy and often necessitating dose escalation. The ideal goal is to deliver the entire dose of therapeutic into the lung with the minimal exposure of other tissues. We attempt to approach this ideal goal by pumping unique immunotherapeutics precisely into lung tissue to comprehensively block activation and differentiation of MF, the key driver of profibrotic extracellular matrix (ECM) deposition and activation of survival cascades, leading to progressive scarring. The goal of this project is to develop and test novel lung precision drug delivery system (LPDDS) targeting endothelial cells caveolae that are actively and specifically pump myofibroblasts (MF)-directed antifibrotics into lungs at microdoses after intravenous (IV) injection. We have identified the cell surface protein THY-1 a precision therapeutic and a major modulator of MF activation and differentiation and characterized its role in resolving fibrosis via synergistic engagement of multiple profibrotic signaling pathways. Based on this, we engineered the first "dual precision" bispecific therapeutic mapp:THY-1 with antibody mediating precise binding/delivery to and penetration of lung tissue via caveolae transcytosis and the other - mediating THY-1'S fibrosis-resolving activity in the lung interstitium where the loss of THY-1 promotes a dysregulated MF phenotype driving fibrosis. To further potentiate antifibrotic effect, we designed mapp:FAP-nintedanib immunoconjugates, where concerted action of THY-1 and nintedanib in the lung parenchyma has even greater power to concentrate their fibrosis-resolving activities at the site of action, potentially reversing fibrosis. Our goal is to explore transendothelial pumping via caveolae to improve therapy of lung diseases at various stages from very early inflammatory to fibrotic. We will optimize lung targeting of our LPDDS through engineering and chemistry and will study their specific lung delivery, penetration, accumulation, and therapeutic impact using multiple imaging techniques (spect-CT, IVM, EM, and IHC). Therapeutic effects will be determined in two RAT models that can reproduce many pathological hallmarks of inflammatory and fibrotic disease stages. Our specific aims are 1) to generate and test in vitro activity of caveolae- and myofibroblast- targeting therapeutics, 2) to assess the lung targeting, imaging and tissue processing of caveolae- and myofibroblast-targeting therapeutics in rodent models of fibrosis, and 3) to test the therapeutic efficacy of caveolae/myofibroblast-targeting therapeutics in lung fibrosis. This work sets a foundation for caveolae-targeted therapies and could begin a paradigm shift from passive to active delivery for many pulmonary diseases.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $764,403 | |
| Amendment | $782,151 | |
| Original award | $805,845 |
Quick answers
Who received award R01HL175948?
R01HL175948 was awarded to Proteogenomics Research Institute For Systems Medicine by National Heart Lung and Blood Institute (National Institutes of Health) on September 17, 2024.
How much is award R01HL175948 worth?
$2,352,399 has been obligated on R01HL175948.
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