CD45 Phosphatase Inhibition as a Treatment for Heart Disease and Fibrosis
Inventors: Joyce Bischoff
Invention Types: Therapeutics, Therapeutics
Research Areas: Allergy/Respiratory/Pulmonary Disease
Keywords: Heart DiseaseFor More Information Contact: Wong, Adrienne
Endothelial-to-mesenchymal transition (EndMT) is a developmental and repair process where endothelial cells lose adhesion with their neighbors, increase their migration and become precursor cells. While CD45 has been implicated in loss of adhesion in hematopoietic cells, it has never been observed on non-embryonic endothelium. A common side-effect of EndMT is fibrosis, which can have serious pathological consequences such as thickened mitral valve leaflets, causing mitral regurgitation, and can result in tissue ossification in patients with cerebral cavernous malformations, intimal thickening at sites of atherosclerosis, arterial calcification, and fibroplasia ossificans progressiva.
Work from Dr. Joyce Bischoff’s lab suggests that pathological EndMT after ischemic injury can be prevented by inhibiting CD45. Using an ovine model of ischemic injury, Bischoff found that CD45 was expressed in endothelial cells after ischemic injury, but not in normal endothelial cells. This result was confirmed in vitro by showing endothelial cells induced to undergo EndMT by TGFβ expressed CD45. Finally, the investigators found that TGFβ-induced EndMT can be blocked by inhibiting CD45 phosphatase activity, as indicated by a decrease of cellular migration and by a loss of other EndMT hallmarks. Drugs based on this discovery have the potential to reduce EndMT-mediated fibrosis after ischemic injury, aid in the prevention of mitral valve disease, and provide a treatment for fibroplasia ossifcans progressiva
• Blocking CD45 activity could decrease the morbidity and mortality rates from heart disease.
• Inhibition of CD45 may provide a much-needed treatment for tissue ossification disorders.
• Heart disease is a leading cause of death in the U.S. Many complications arise from tissue fibrosis after the initial injury. The inhibition of CD45 represents a first-in-class approach to treat heart disease through the inhibition of the endothelial-to-mesenchymal transition.
• Fibroplasia ossificans progressiva is currently an untreatable rare pediatric genetic disorder and may qualify for a rare pediatric disease accelerated review by the FDA.
Licensing; Sponsored Research to test novel small-molecule or antibody CD45 inhibitors in ischemia model
Key Publications: Bishchoff J, Casanovas G, Wylie-Sears J, et al. CD45 expression in mitral valve endothelial cells after myocardial infarction. Circ Res. 2016 Nov 11;119(11)
IPStatus: Pat. Pend.