Targeting TBX4 for Tissue Fibrosis

Tech ID: nob000902

 

Introduction

This invention discloses a new treatment target 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 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

T-box gene 4 (TBX4) is a mesenchymal-specific transcription factor that is expressed early during embryonic development and is essential for airway branching. Dr. Noble and colleagues studied the involvement of TBX4 in adult lung fibrosis and discovered:

 

• TBX4-lineage cells give rise to a diversity of cells such as fibroblasts and smooth muscle cells.

 

• TBX4-lineage cells expand and form clonal-like patches within fibrotic foci.

 

• TBX4-lineage cells are major contributors to myofibroblast accumulation. Specific deletion of TBX4-lineage cells or the TBX4 gene in either collagen or alpha smooth muscle actin (αSMA) expressing fibroblasts significantly attenuated lung fibrosis.

 

• TBX4 enhances fibroblast invasiveness through hyaluronan synthase 2 (HAS2) pathway, a known pathway that contributes to fibrosis development.

 

Collectively, this data suggests that TBX4 is an important regulator of fibrogenic potential of diverse cell types that contribute to myofibroblast accumulation.

 

Applications

• These findings identified TBX4 as a new target for lung fibrosis treatment. Therapeutic molecules can be developed to target TBX4.

 

Intellectual Property

PCT application PCT/IB2016/056575 nationalized in US and EU.

 

Selected Publication

Xie et al. Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. J Clin Invest. 2016, 126(8): 3063-3079 [Link]

 

Figure: Knockout of TBX4 in collagen (left panel) or alpha smooth muscle actin (right panel) expressing cells attenuates lung fibrosis as shown by decreased collagen deposition after Bleomycin induced lung injury after 21 days.

 

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