Extracellular Matrix Modulators as Therapeutics for Prevention of Vascular Leakage
Inventors: Don Ingber, Akiko Mammoto
Invention Types: Therapeutics
Research Areas: Allergy/Respiratory/Pulmonary Disease, Cardiovascular/Cardiology, Oncology/Hematology
Keywords: Heart Disease, Organ TransplantFor More Information Contact: Ives, Catherine L.
Vascular permeability is tightly regulated and critical for normal organ function throughout life. Consequently, compromised vascular barrier function contributes to or complicates many life-threatening pathological conditions including acute respiratory distress syndrome (ARDS), sepsis, organ failure, cancer, and atherosclerosis. To address this challenge, researchers in the Ingber lab have discovered that vascular leakage can be controlled by altering extracellular matrix (ECM) structure using chemicals or biologics, and therefore can be manipulated in a clinically impactful manner.
The Ingber lab has discovered that physical changes in the ECM directly impact cell-cell junctions and vascular permeability, and they have demonstrated that the ECM is mechanically stiffer in disease conditions, such as pulmonary edema and cancer, where increased vascular leakage is observed. Importantly, they showed that by increasing the flexibility of these abnormally stiffened ECMs, for example, by inhibiting collagen cross-linking with chemical modulators, they can normalize vascular barrier function. Moreover, they used this approach to prevent endotoxin-induced pulmonary edema in an animal model. The same approach could potentially be used to alter drug delivery across vascular barriers.
• Novel methods for manipulating the vascular permeability of a tissue or organ through modulation of the ECM. For example, through administration of lysyl oxidase modulators or agents that alter ECM production or degradation.
• Innovative therapeutic approach for diseases characterized by abnormal vascular permeability including ARDS, sepsis, cancer, organ failure, atherosclerosis, and others.
• A novel method for increasing vascular permeability to facilitate drug delivery to specific target sites.
There are currently no approved therapies for ARDS or any other diseases caused by abnormal vascular permeability.
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Mammoto A, Mammoto T, Kanapathipillai M, Yung C-W, Jiang E, Jiang A, Lofgren K, Gee E P.S., Ingber DE, 2013. Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics. Nature communications 4: 1759.
Bishof AG, Yüksel D, Mammoto T, Mammoto A, Krause S, Ingber DE, 2013. Breast cancer normalization induced by embryonic mesenchyme is mediated by extracellular matrix biglycan. Integr Biol (Camb) 5: 1045
Werfel J, Krause S, Bischof AG, Mannix RJ, Tobin H, Bar-Yam Y, Bellin RM, Ingber DE, 2013. How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression. PLoS One 8: e76122
IPStatus: Pat. Pend.