Using Deferiprone to Target Mitochondrial Iron for the Treatment of Pulmonary Diseases
- 详细技术说明
- This invention discloses the use of the iron chelator, deferiprone for targeting mitochondrial iron as a therapeutic target for IRP2-regulated cigarette smoke-induced bronchitis and emphysema or chronic obstructive pulmonary disease (COPD).
- *Abstract
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TechnologyOverview
COPD presents as a complex debilitating lung disease thatencompasses a variety of clinical and pathologic phenotypes ranging from airwayinflammation (chronic bronchitis) to destruction of lung tissue (emphysema) andremodeling of the small airways. The pathogenesis of COPD remains poorlyunderstood, but involves aberrant inflammatory and dysregulated cellularresponses of the lung to cigarette smoke (CS) exposure. CS exposure remains the greatestenvironmental risk factor for COPD; however, multiple studies have suggestedthat genetic factors influence COPD susceptibility.
The iron-responsive element bindingproteins (IRPs) IRP1 and IRP2 regulate cellular iron homeostasis, with IRP2serving as the major regulatory protein in mammalian cells. IRPs have importantphysiological roles in the duodenum, spinal cord and central nervous system,and in the pathogenesis of pulmonary hypertension and neurodegenerativediseases. The inventors previouslyidentified IRP2 as a leading candidate COPD susceptibility gene based ongenome-wide association studies (GWAS), and also demonstrated that IRP2 proteinis increased in the lungs of COPD subjects. IRP2 is located within a cluster ofgenes on chromosome 15q25, which includes several components of the nicotinicacetylcholine receptor.
The inventors integrated human COPDexpression data with experimental mouse models of COPD to show that exposure toCS raised the levels of IRP2, which in turn led to mitochondrial ironaccumulation, along with aberrant activation of the enzyme cytochrome c oxidase(COX). The resultant mitochondrial dysfunction causes defective mucociliaryclearance and COPD. They also show that mitochondrial iron chelation using thesiderophore deferiprone alleviates established disease in a model of CS-inducedpulmonary inflammation and injury (experimental COPD).
Potential Applications
Treatment with deferiprone could provide a much-needed novel therapeuticapproach for COPD.
Advantages
Deferiprone has already been approved for human use by the US FDA, whichcould reduce the clinical development time required to develop deferiprone forthis proposed, new indication.
- *Licensing
- Brian J. Kelly, Directorbjk44@cornell.edu646-962-7045
- 其他
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Publication
Cloonan S. M., et. al., Mitochondrial ironchelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice.Nature Medicine, 2016.
- 国家/地区
- 美国
