Targeting TLR4 and Hyaluronan Synthase 2 for Lung Fibrosis

Tech ID: nob001106

 

Introduction

This invention discloses a new treatment strategy for idiopathic pulmonary fibrosis (IPF). Progressive tissue fibrosis is a major cause of morbidity, and IPF is a terminal illness characterized by accumulation of myofibroblast cells and unremitting extracellular matrix deposition in the lungs. IPF is the most common form of fibrotic lung disease with a prevalence of 14.0–42.7 cases per 100,000 individuals in the United States and a median survival of 2.5–3.5 yr with limited treatment options. Examples of non-medication based interventions for IPF include pulmonary rehabilitation, long-term oxygen therapy, mechanical ventilation, and lung transplantation. Of these treatments, the only intervention that improves survival in select patients with IPF is a lung transplant. However, lung transplantation is not without significant risks. Currently approved medications can slow the decline in patient’s lung function but do not change the prognosis of disease. Therefore, new treatment strategies are highly desired for this unmet medical need.

 

Technology Description

The lung alveolar epithelium is vulnerable to injury and employs stem-cell-progenitors for timely repair. IPF is believed to result from numerous micro-injuries and improper regeneration of alveolar epithelium. Dr. Noble and colleagues investigated the role of Type 2 alveolar epithelial cells (AEC2s), stem cells involved in lung repair, in IPF development. Their key discoveries include:

 

•  Expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis.

 

•  Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality.

 

•  Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity.

 

These results support the concept that IPF is primarily a disease of AEC2 stem cell failure and identify key pathways in this process. The inventors propose new treatment strategy based on these discoveries.

 

Applications

•  This technology can be developed into new treatment strategies for idiopathic pulmonary fibrosis.

 

Intellectual Property

US utility application 16/150,379 filed.

 

Selected Publication

Liang et al. Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice. Nature Medicine. 2016, 22: 1285-1293 [Link]

 

Figure: AEC2s from lung tissue of IPF patients have lower colony forming efficiency (CFE) and form smaller colonies relative to AEC2s from healthy donors.

 

Patent Information:
For Information, Contact:
Wenyue Du
Senior Associate - IP Management & Licensing
310-423-2241
wenyue.du@cshs.org
Inventors:
Paul Noble
Jiurong Liang
Dianhua Jiang
Keywords:
Inflammatory Disorders