Use of Prolyl Hydroxylase Domain Inhibitors as Antifibrotic Agents in Pulmonary Fibrosis
Invention Summary
The inventor has discovered the use of HIF prolyl hydroxylase domain inhibitors, such as roxadustat,for the treatment of pulmonary fibrosis.
Technology Overview
Pulmonary fibrosis (PF) is scarring of lung tissue and idiopathic pulmonary fibrosis (IPF), which belongs to a large group of more than two hundred lung diseases, characterized by irreversible fibrosing interstitial pneumonia of unknown cause, occurs in older adults. IPF has a median survival of 3.8 years. In the US, 100,000 people are living with the disease and 1 in 1,000 are diagnosed with IPF annually. Treatment options are limited to halting progression of the disease and oxygen supplementation to improve symptoms and organ function. The clinical course of IPF includes acute exacerbations often with hospitalization.
The relationship of mast cells to the pathogenesis of lung fibrosis remains undefined despite their abundance in IPF. Mast cell density is higher in IPF lungs compared to other fibrotic interstitial lung diseases and normal lungs, and the mast cells are active and degranulating. Clinically, there is a correlation between severity of IPF and mast cell number. The inventor’s previous work in a murine model of PF showed that mast cells play a significant role in pathologic collagen deposition. In the lungs, mast cells are found closely apposed to fibroblasts, the cells responsible for collagen synthesis and secretion. Mast cell mediators can be fibrogenicvia receptor-mediated stimulationof collagen synthesis in human lung fibroblasts. The inventor has discovered an additional and novel mast cell-fibroblast mode of communication – the ability of mast cell exosomes to be taken up by fibroblasts and stimulate collagen secretion. Hence, a novel fibrogenic pathway by which mast cells and fibroblasts communicate in the lung represents an additional and here-to-for unidentified mechanism that promotes fibrosis.
Both the exosome and receptor mediated fibroblast activation pathways require the post-translational modification of pre-pro-collagen to pro-collagen. The assembly of collagen into its mature, triple helical form requires prolyl hydroxylation, which is the conversion of proline residues in pre-pro-collagen to hydroxyproline to form pro-collagen. Collagen prolyl-4-hydroxylases (c-P4Hs) are the enzymes responsible for the prolyl hydroxylation. C-P4H enzymes are members of the superfamily of 2-oxoglutarate (2-OG)–dependent dioxygenases. Another group of prolyl 4-hydroxylases are the prolyl hydroxylase domain (PHD) enzymes associated with hypoxia inducible factors (HIFs). HIF PHD enzymes are structurally related to c-P4H and also belong to the superfamily of 2-OG-dependent dioxygenases. This invention encompasses an anti-fibrotic role for HIF PHD inhibitors like roxadustat, as a means to blockc-P4H activity thereby preventing excessive collagen secretion by fibroblasts. This invention shows that the potent small HIF PHD inhibitor roxadustatdecreases the secretion of collagen from stimulated fibroblasts.
Potential Applications
This invention identifies a pathway independent, novel therapeutic target representing the rate-limiting step in pro-collagen and collagen formation encompassing a potential treatment option for lung fibrosis.
Advantages
Multiple Phase 1 and 2 clinical trials (>than 1400 patients) have been completed forroxadustat in a different indication. Safety data from these trials could be used to reduce the clinical development time required to develop roxadustat for this proposed, new indication.
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