Rousso-Noori L.,Weizmann Institute of Science |
Knobler H.,Metabolic Unit |
Levy-Apter E.,Weizmann Institute of Science |
Kuperman Y.,Weizmann Institute of Science |
And 7 more authors.
Molecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation. © 2011 Elsevier Inc. Source
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 1.21M | Year: 2011
DESCRIPTION (provided by applicant): Over 90% of cancer patients that enroll in Phase I or II clinical trials experience no benefit from the experimental therapies, yet are exposed to drug toxicity and other challenges related to treatment. For over 50 years, physicians have used patient-specific information about drug resistance and sensitivity to select antibiotics for patients with infections, but this personalized approach has evaded the oncology community because cancer cell behavior in vitro drug sensitivity assays does not correlate with in vivo response to therapy in most cases. We have developed technologies that enable oncology drug sensitivity/resistance testing of multiple drugs or drug combinations in vivo during the days prior to surgical resection of a tumor. This approach allows drugs to interact with cancer cells while the latter are in their native tumor microenvironment. Our broad long-term goal is to develop reliable in vivo-based oncology drug sensitivity/resistance assays for patients with many types of solid tumors. Our overall goal of the STTR Phase I and II projects are to develop and test devices that are suitable for human lymphoma patients and to initiate human clinical trials. Our Specific Aim for the Phase I portion is to develop a single use (disposable) porous needle array and demonstrate that it meets drug delivery precision specifications. Provided that quantitative milestones are met in Phase I, Phase II will proceed with the following Aims: Aim 1) To develop a prototype suitable for use in human lymphoma patients; and Aim 2) to conduct a pilot first in humans clinical trial. The significance of the proposed work is that it will reduce the frequency of cancer patients being exposed to drugs that cause toxicity but offer no clinical benefit. The commercialization potential is described in a comprehensive business plan. We provide letters from highly respected individuals in the biotechnology, life sciences and personalized medicine fields to attest to the commercial potential of this technology. PUBLIC HEALTH RELEVANCE: Project Narrative It is estimated that approximately 1.4 million new cases of cancer will be diagnosed in the United States in 2008. Improved methods for prioritizing cancer therapeutics based on patient-based indicators of efficacy are needed. We are proposing to develop a device which enables comparison of multiple drugs or combinations in vivo, with the tumor micro-environment intact. The long-term goal of this research is to develop reliable in vivo- based oncology drug sensitivity/resistance assays for patients with many types of solid tumors. This technology will reduce the frequency of cancer patients being exposed to drugs that cause toxicity but offer no clinical benefit. This personalized treatment approach will improve patient outcome and enhance the quality of care for millions of individuals that suffer from cancer.
Presage Biosciences, Inc. | Date: 2013-12-05
An administration device comprising an array of needles, one or more fluid agents, and at least one hydrogel is described. The device can simultaneously deliver a plurality of fluid agents along respective axes into a tissue. The use of hydrogel leads to constrained delivery of the fluid agents. The constrained delivery of an agent is also achieved by depositing a drug implant into a tissue. The effect of an agent on the tissue can be evaluated thereafter. In addition, the invention is directed to treating muscle diseases by delivering a therapeutic agent in vivo, and the use of reporter tissues for candidate drug evaluation, detecting and characterizing resistance.
Presage Biosciences, Inc. | Date: 2013-11-13
Methods for multiplexed delivery of agents to a solid tissue in vivo followed by assessment of efficacy with mass spectrometry are described.
Presage Biosciences, Inc. | Date: 2013-08-08
Disclosed herein are devices and methods for delivering agents to a solid tissue.