Columbia University

The Brigham and Women's Hospital, Inc.

Thomas Jefferson University

Other

Massachusetts Institute of Technology

Ira A Tabas

Kevin Jon Williams

Omid C Farokhzad

Scott L Schissel

Robert Samuel Langer

Pedro M Valencia

Lale Ozcan

Xiaoding Xu

Xueqing Zhang

Nazila Kamaly

Mingming Ma

Xiaoyang Xu

Xiaobo Wang

Gabrielle Beth Fredman

Yiguo Wang

The present invention relates to methods and compositions for specifically modulating the Hippo pathway transcription factor TAZ (WWTR1), as a therapeutic target for inhibiting or preventing liver conditions including the progression of steatosis-to-NASH in a patient.

Therapeutic targets involved in the progression of nonalcoholic steatohepatitis (NASH)

Sub-100 micron multimodal nanoparticles have four main components: 1) a target element (peptides, lipids, antibodies, small molecules, etc.) that can selectively bind to cells, tissues, or organs of the body; 2) a diagnostic agent such as a fluorophore or NMR contrast agent that allows visualization of nanoparticles at the site of delivery and/or a therapeutic or prophylactic agent; 3) an outside 'stealth' layer that allows the particles to evade recognition by immune system components and increase particle circulation half-life; and 4) a biodegradable polymeric material, forming an inner core which can carry therapeutics and release the payloads at a sustained rate after systemic, intraperitoneal, or mucosal administration. These particles possess excellent stability, high loading efficiency, multiple agent encapsulation, targeting and imaging. They are targeted to sites of, or associated with, inflammation caused by a disease, disorder; trauma, chemotherapy or radiation.

Targeted polymeric inflammation-resolving nanoparticles

The present invention relates to methods of treating or preventing a metabolic disorder in a subject, methods of treating or preventing coronary artery disease in a subject with a metabolic disorder, as well as methods of reducing hepatic glucose production in a subject. Such methods include, but are not limited to, the administration to the subject of inhibitors or activators of CaMKII, IP3Rs, calcineurin, p38, MK2/3, HDAC4, Dach1, Dach2, or any combination thereof. The invention also provides methods of identifying a compound that inhibits the activity of CaMKII, IP3Rs, calcineurin, p38, MK2/3, HDAC4, Dach1 or Dach2, or reduces the activity and/or activation of CaMKII, IP3Rs, calcineurin, p38, MK2/3, HDAC4, Dach1 or Dach, or activates CaMKII, IP3Rs, calcineurin, p38, MK2/3, HDAC4, Dach1 or Dach2.

Method of treating a metabolic disorder induced by obesity in a subject in need thereof by administering MK2/3 inhibitors

The present invention provides for a method for treating a subject suffering from a condition associated with an extracellular zinc sphingomyelinase activity which comprises administering to the subject an amount of a zinc sphingomyelinase inhibitor effective to decrease extracellular zinc sphingomyelinase activity in the subject and thereby treat the subject. The present invention also provides for a method for determining whether a compound inhibits an activity of an extracellular zinc sphingomyelinase involving ceramide formation which comprises: (a) contacting a sample containing zinc sphingomyelinase under acidic pH conditions known to be associated with the activity of such zinc sphingomyelinase, with: (i) a substrate of the zinc sphingomyelinase enzyme, and (ii) the compound being evaluated; (b) measuring the ceramide in the sample from (a); (c) determining the amount of zinc sphingomyelinase activity in the sample based on the concentration of ceramide measured in step (b); and (d) comparing the amount of sphingomyelinase activity determined in step (c) with the amount of sphingomyelinase activity determined in the absence of the compound, so as to determine whether the compound inhibits the activity of zinc sphingomyelinase.

Method for treating a subject suffering from conditions associated with an extracellular zinc sphingomyelinase

Genes and polypeptides encoded thereby of human chondroitin 6-sulfotransferase are provided. Vectors and host cells comprising these genes and transgenic animals capable of expressing them are also provided. In addition, methods of identifying polymorphic chondroitin 6-sulfotransferase in humans and activators or inhibitors of this enzyme are provided.

Human gene encoding human chondroitin 6-sulfotransferase

The present invention provides for a method for treating a subject suffering from a condition associated with an extracellular zinc sphingomyelinase activity which comprises administering to the subject an amount of a zinc sphingmyelinase inhibitor effective to decrease extracellular zinc sphingomyelinase activity in the subject and thereby treat the subject. The present invention also provides for a method for determining whether a compound inhibits an activity of an extracellular zinc sphingomyelinase involving ceramide formation which comprises: (a) contacting a sample containing the zinc sphingomyelinase under acidic pH conditions known to be associated with the activity of such zinc sphingomyelinase, with: (i) a substrate of the zinc sphingomyelinase enzyme, and (ii) the compound being evaluated; (b) measuring the concentration of ceramide in the sample from (a); (c) determining the amount of zinc sphingomyelinase activity in the sample based upon the concentration of ceramide measured in step (b); and (d) comparing the amount of sphingomyelinase activity determined in step (c) with the amount of sphingomyelinase activity determined in the absence of the compound, so as to determine whether the compound inhibits the activity of zinc sphingomyelinase.

Method for treating a subject suffering from a condition associated with

The present invention provides a purified compound of the structure; ##STR1## wherein R may be palmitoyl or steroyl. The invention also provides compositions comprising an admixture of the foregoing palmitate and stearate esters. The invention also provides a compound of the structure: ##STR2## The invention further provides pharmaceutical compositions including the aforementioned compounds and compositions and methods of inhibiting the acyl CoA: cholesterol acyltransferase catalyzed conversion of cholesterol to cholesteryl esters.

Growing community of inventors

New City, NY, United States of America

Ira A Tabas