A New Alternatively Spliced Version of Human MD2 Which is Secreted and Can Inhibit TLR4 Signaling

Tech ID: ard000356

 

Introduction

LPS is a major component of the outer membrane of Gram-negative bacteria. TLR4-LPS signaling pathway is involved in the detection of microbial pathogens and instigation of an appropriate innate and subsequent adaptive immune response. This pathway requires the coreceptor myeloid differentiation factor (MD)-2.

This invention is a novel therapeutic candidate to treat human disease characterized by an overly exuberant or chronic immune response to LPS (bacterial infection) or house dust mite induced allergic asthma.

 

Technology Description

Inventors discovered a novel alternatively spliced isoform of human MD-2, termed MD-2 short (MD-2s) which negatively regulates LPS-mediated TLR4 signaling. MD-2s.

• In vitro data in HEK293 cells: MD-2s fails to mediate LPS-dependent NF-kB activation and IL-8 secretion.

• In vivo mouse data:  MD-2s inhibits lung inflammation induced by LPS in vivo.

• In vivo mouse data: MD-2s inhibits HDM induced allergic lung inflammation in vivo.

 

Advantages/Novelty

• Current antibiotics for Gram negative sepsis and or lung infection are not sufficient to prevent, block and reverse bacterial endotoxin mediated lung injury and inflammation during Adult Respiratory Disease Syndrome (ARDS), which has a very high mortality and morbidity.

• An anti-inflammatory molecule to down modulate the lung inflammation would be a significant benefit to existing care for sepsis and or Gram negative pneumonia induced ARDS.

• In addition, the use of the inhibitory (short MD2) in House Dust mite induced allergic asthma would provide a novel target to treatment of Allergic Asthma.

 

Applications

• The technology can be translated into potential drug discovery efforts to develop novel class of drugs against a variety of bacterial infections mediated through the LPS-TLR4/MD2 signaling pathway as well as House Dust mite induced Allergic asthma that is also MD2 signaling dependent.

• Recombinant short MD2 (which acts as a natural inhibitory molecule) can be turned into a drug (either soluble for intravenous or aerosol for targeted lung delivery). The short MD2 can also be put into existing nanoparticles for more effective targeting into specific tissues either IV or as an aerosol.

 

Intellectual Property

US 8,546,324 granted. US 14/639,782 pending.

 

Publications

• Gray et al. Identification of a novel human MD-2 splice variant that negatively regulates lipopolysaccharide-induced TLR4 signaling. The Journal of Immunology. 2010, 184:6359-6366. [LINK]

• Tumurkhuu et al. Alternatively spliced myeloid differentiation protein-2 (MD-2s) protein inhibits TLR4- mediated lung inflammation. The Journal of Immunology. 2015, 194(4):1686-94. [LINK]

 

Patent Information:
For Information, Contact:
Wenyue Du
Associate - IP Management & Licensing
310-423-2241
wenyue.du@cshs.org
Inventors:
Moshe Arditi
Pearl Gray
Keywords:
Infectious Diseases