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Use of Natural or Synthetic Retinoid Receptor Ligands to Affect Mental Capacity (S01020.pdf)

Inventors
Sharoni Jacobs and Ronald M. Evans

Applications
Molecular Neurobiology, Drug Discovery, CNS

The invention provides methods of affecting neural function or memory in a subject by administering compositions of natural or synthetic retinoid receptor ligand, or a precursor or derivative thereof, optionally in the presence of one or more neuromodulatory agents. Subjects include those persons who exhibit symptoms such as amnesia, dementia, or age-related memory loss. The invention further provides methods of screening compounds to determine those which modulate retinoid receptor activity in the central nervous system.

References
PNAS 98(20):11714-9 (September 2001)

Patent Status:
U.S. Application Pending

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S01020

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Novel Histone Deacetylase and Uses Therefor (S00021.pdf)

Inventors
Ronald Evans, Hung-Ying Kao, Michael Downes, and Peter Ordentlich

Applications
Gene Expression, Oncology, Drug Discovery

The histone deacetylases are involved in cell-cycle regulation and differentiation and have been implicated in repression of gene expression. The invention relates to the identification, isolation, sequencing and characterization of a new member of the histone deacetylase family, as well as its transcripts, gene products, associated sequence information, and related genes. The invention also relates to methods for detecting and diagnosing carriers of normal and mutant alleles of these genes, methods for detecting and diagnosing diseases such as cancer, methods of identifying genes and proteins related to or interacting with such genes and proteins, methods of screening for potential therapeutics for diseases, methods of treatment for diseases and to cell line and animal models useful in screening for and evaluating potentially useful therapies for diseases.

References
Genes Dev 14(1):55-66 (January 2000)

Patent Status:
U.S. Patent Number 6,673,587 issued January 6, 2004

License Terms
Nonexclusive licenses available

Reference Number: S00021

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Gene Transfer Vectors and Expression Systems for Inducible Expression of Transfected Genes (S99028B.pdf)

Inventors
Ronald Mark Evans, Inder Mohan Verma, Enrique Saez, Francesco Galimi

Applications
Gene Expression

The present invention provides inducible gene transfer systems and gene transfer vectors for the safe and effective transfer and expression of genes in mammalian cells, and for a very high level of control of expression of the transferred genes. The inducible gene transfer systems of the present invention may be lentiviral vectors comprising a self-inactivating 5' LTR, a modulator-responsive promoter, a nuclear import signal, a promoter operatively associated with a nucleic acid encoding a modulator-responsive receptor, an RNA stabilizing element, and a self-inactivating 3' LTR. Thus, the present invention provides vectors for packaging and delivering DNA to both dividing and non-dividing cells. The present invention also provides methods for treating subjects with the gene transfer systems of the present invention, and cells containing the gene transfer systems.

References


Patent Status:
U.S. Application Published as 2004-0235169

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S99028B

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Formulations Useful for Modulating Expression of Exogenous Genes in Mammalian Systems, and Products Related Thereto (S98002.pdf)

Inventors
Ronald Mark Evans, Enrique Saez

Applications
Gene Expression

In accordance with the present invention, there are provided various methods for modulating the expression of an exogenous gene in a mammalian subject employing modified ecdysone receptors. Also provided are modified ecdysone receptors, as well as homomeric and heterodimeric receptors containing same, nucleic acids encoding invention modified ecdysone receptors, modified hormone response elements, gene transfer vectors, recombinant cells, and transgenic animals containing nucleic acids encoding invention modified ecdysone receptor.

References
Current Opinion in Biotechnology 8(5):608-616 (1997)

Patent Status:
U.S. Patent Number 6,333,318 issued December 25, 2001
U.S. Application Pending

License Terms
Nonexclusive field of use licenses negotiable

Reference Number: S98002

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Products Useful for Modulating Expression of Exogenous Genes in Mammalian Systems (S98001.pdf)

Inventors
Ronald Evans and David No

Applications
Gene Expression

This invention relates to various methods for modulating the expression of an exogenous gene in a mammalian subject employing modified ecdysone receptors. The invention method is useful in a wide variety of applications where inducible in vivo expression of an exogenous gene is desired, such as in vivo therapeutic methods for delivering recombinant proteins into a variety of cells within a patient. Advantages of ecdysteroid use include the lipophilic nature of the compounds, short half-lives, and favorable pharmacokinetics that prevent storage and expedite clearance. The invention also relates to modified ecdysone receptors, nucleic acids encoding modified ecdysone receptors, modified ecdysone response elements, gene transfer vectors, recombinant cells, and transgenic animals containing nucleic acids encoding modified ecdysone receptor.

References
Proc. Natl. Acad. Sci. 93: 3346-3351 (1996)

Patent Status:
U.S. Patent No. 6,723,531 issued April 20, 2004
U.S. Patent Application Pending

License Terms
Nonexclusive field of use licenses negotiable

Reference Number: S98001

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Methods for the Use of Inhibitors of Co-Repressors for the Treatment of Neoplastic Diseases (S97034.pdf)

Inventors
Ronald Mark Evans, Laszlo Nagy, Richard J. Lin

Applications
Drug Discovery, Oncology

In accordance with the present invention, it has been discovered that histone deacetylase associates with hormone receptor complexes and contributes to the repression thereof. It has further been discovered that exposure of a repressed system to histone deacetylase inhibitors relieves this repression, and that in combination with a ligand for a member the steroid/thyroid superfamily of receptors, the differentiation effects of retinoids are enhanced. Thus, histone deacetylase inhibitors have been found to be useful for the activation of genes responsive to hormone receptors and to counteract the oncogenic functions of oncogenic proteins. In accordance with another aspect of the invention, formulations useful for modulation of hormone-mediated processes have been developed. In addition, assays have been developed for the identification of compounds useful to modulate the above-described processes as well as methods of employing such compounds to modulate or enhance hormone mediated processes, such as human cancers.

References
Nature 391(6669):811-4 (February 1998)

Patent Status:
U.S. Patent Number 6,706,762 issued March 16, 2004

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S97034

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Compounds Useful for the Modulation of Processes Mediated by Nuclear Hormone Receptors, Methods for the Identification and Use of Such Compounds (S97012.pdf)

Inventors
Ronald Evans and Laszlo Nagy

Applications
Oncology, Drug Discovery and Development

It has been discovered that histone deacetylase associates with hormone receptor complexes and contributes to the repression thereof. It has further been discovered that exposure of a repressed system to histone deacetylase inhibitors relieves this repression. Thus, histone deacetylase inhibitors have been found to be useful for the activation of genes responsive to hormone receptors. The invention includes compositions for the treatment of cancer, which are made up of a ligand for a member of the steroid/thyroid hormone superfamily of receptors and a histone deacetylase inhibitor. Preferred ligands are ligands for retinoid receptors (e.g., all-trans retinoic acid, 9-cis retinoic acid), ligands for thyroid hormone receptors or ligands for vitamin D3 receptor. Preferred inhibitors included histone deacetylase inhibitors (e.g., Trichostatin A, Trapoxin), and chromatin remodeling machinery inhibitors.

References
Cell 1997 May 2;89(3):373-80;
Nature 1998 Feb 19;391(6669):811-4

Patent Status:
U.S. Patent No. 6,387,673 issued May 14, 2002

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S97012

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Use of RAR Antagonists as Modulators of Hormone Mediated Processes (S96028.pdf)

Inventors
Ron Evans, Laszlo Nagy, and Peter Tontonoz

Applications
Cardiovascular, Obesity. Drug Discovery and Development

Retinoic acid receptor (RAR) antagonists are capable of modulating processes mediated by non-RAR members of the steroid/thyroid hormone receptor superfamily including permissive receptors such as PPARs (e.g., PPAR-alpha, PPAR-delta and PPAR-gamma). It has been discovered that RAR antagonists, in combination with agonists for members of the steroid/thyroid hormone receptor superfamily, are capable of inducing and/or enhancing processes mediated by such members. Such compositions will modulate the activity of permissive heterodimers. Permissive heterodimeric members of the steroid/thyroid hormone receptor superfamily include PPAR:RXR, LXR:RXR, NGFI-B:RXR, NURR1:RXR, FXR:RXR, BXR:RXR, SXR:RXR. For example, PPAR regulates genes involved in fatty acid degradation. This is blocked by retinoid agonists. In contrast, an RAR antagonist can stimulate PPAR signaling. Accordingly, a composition composed of an RAR antagonist and a PPAR agonist could represent a unique approach to treat PPAR controlled syndromes such as cardiovascular disease, hyperlipidemia, obesity or insulin resistance which are characterized by altered levels of fatty acids or their metabolites.

Patent Status:
U.S. Patent Number 6,236,993 issued August 20, 2002

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S96028

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Treatment of Disease States which Result from Neoplastic Cell Proliferation Using PPAR-gamma Activators and Compositions Useful Therefor (S96024.pdf)

Inventors
Ron Evans, Laszlo Nagy, and Peter Tontonoz

Applications
Oncology, Drug Discovery and Development

Neoplastic cell proliferation is the underlying cause of a wide variety of diseases, e.g., breast cancer, leukemia, colon cancer, prostate cancer. Traditional approaches to treatment of neoplastic cell proliferation include surgery, chemotherapy and radiotherapy. Induction of terminal differentiation represents a promising alternative to conventional methods of treatment for certain malignancies. It has been discovered that PPAR-gamma is expressed consistently in tissues associated with a variety of disease states which result from neoplastic cell proliferation. Maximal activation of PPAR-gamma with exogenous ligand promotes terminal differentiation of primary cells which are otherwise subject to neoplastic cell proliferation. Thus, cells undergoing neoplastic cell proliferation can be induced to differentiate, thereby blocking further proliferation. It has also been discovered that RXR-specific ligands are potent agents for induction of differentiation of cells expressing the PPAR-gamma/RXR-alpha heterodimer and that simultaneous treatment of cells subject to neoplastic cell proliferation with a PPAR-gamma-selective ligand, in combination with an RXR-specific ligand, results in an additive stimulation of differentiation. The invention includes compounds and compositions which could be useful for the treatment of breast cancer, leukemia, colon cancer and prostate cancer.

References
PNAS USA 1997 Jan 7; 94(1):237-41

Patent Status:
U.S. Patent Number 6,646,008 issued November 11, 2003
U.S. Application Pending

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S96024

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Treatment of Liposarcomas Using a Combination of Thiazolidinediones and Retinoid X Receptor Selective Agonists (S96023.pdf)

Inventors
Ron Evans, Peter Tontonoz, and Barry Forman

Applications
Oncology, Drug Discovery and Development

Liposarcoma is the most common soft tissue malignancy in adults, accounting for at least 20% of all sarcomas in this age group. Localized disease is treated primarily with surgery, often in combination with radiotherapy. Metastatic liposarcoma is associated with an extremely poor prognosis, with average five year survival ranging from 70% to 25%, depending on the type of tumor. The development of effective, noninvasive methods for treating liposarcomas would represent a significant advancement in the therapeutic arts. It has been discovered that PPAR-gamma is expressed consistently in each of the major histologic types of human liposarcoma. Maximal activation of PPAR-gamma with exogenous ligand (a thiazolidinedione or derivative thereof) promotes terminal differentiation of primary human liposarcoma cells, thereby blocking further proliferation. It has also been discovered that RXR-specific ligands are potent adipogenic agents in cells expressing the PPAR-gamma/RXR-alpha heterodimer and that simultaneous treatment of liposarcoma cells with a thiazolidinedionyl moiety (a PPAR-gamma-selective class of compounds) and an RXR-specific ligand results in an additive stimulation of differentiation. The invention includes compositions useful for the treatment of liposarcomas.

References
PNAS USA 1997 Jan 7; 94(1):237-41

Patent Status:
U.S. Patent Number 6,586,455 issued July 1, 2003

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S96023

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Inducible Toxic Phenotype in Transgenic Cell Populations (S95055.pdf)

Inventors
Ronald Evans, Emiliana Borrelli, Richard Heyman

Applications
Drug Discovery and Development, Transgenic Animals

This invention relates to a novel selective method for inducibly and selectively ablating specific cell lineages in transgenic cell populations, e.g., in transgenic animals. The new negative selection method, which permits the production of stable transgenic perigees, and thus can be used at various stages of development of a transgenic cell population, allows both the timing and degree of cellular ablation to be controlled. This method can be used for a variety of therapeutic applications, as well as to study cell lineages and organogenesis, plus the capacity that residual stem cells have for regeneration.

References
Proc. Natl. Acad. Sci. 85: 7572-7576 (1988)

Patent Status:
U.S. Patent No. 6,677,311 issued January 13, 2004

License Terms
Exclusive, Partially Exclusive, Nonexclusive license negotiable

Reference Number: S95055

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Methods of Modulating the Expression of Genes Using Ultraspiracle Receptor (S95034.pdf)

Inventors
Ronald Mark Evans, Michael B. McKeown, Anthony Eugene Oro, William A. Segraves, Tso-Pang Yao

Applications
Gene Expression

In accordance with the present invention, it has been discovered that various members of the steroid/thyroid superfamily of receptors can interact with the insect-derived ultraspiracle receptor, to form multimeric species. Accordingly, the interaction of at least one member of the steroid/thyroid superfamily of receptors with at least the dimerization domain of the ultraspiracle receptor modulates the ability of said member of the steroid/thyroid superfamily of receptors to transactivate transcription of genes maintained under hormone expression control in the presence of the cognate ligand for said member of the superfamily.

Patent Status:
U.S. Patent Number 6,265,173 issued July 24, 2001
U.S. Application Allowed

License Terms
Exclusive, Nonexclusive license negotiable

Reference Number: S95034

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Selective Modulators of PPAR-gamma and Methods for the Use Thereof (S95031.pdf)

Inventors
Ron Evans and Barry Forman

Applications
Cardiovascular, Obesity, Drug Discovery and Development

Because obesity is associated with the development of serious medical conditions, including non-insulin-dependent diabetes mellitus, hypertension, coronary artery disease, hyperlipidemias and certain malignancies, it is important that compounds to control adiposity are identified. The conversion of fibroblasts into cells of the adipose lineage is induced by expression of the orphan nuclear receptor PPAR-gamma. Accordingly, an endogenous PPAR-gamma ligand may be an important regulator of adipogenesis. This invention reveals PPAR-gamma as a drug target and relates to a class of compounds which are capable of selectively modulating processes mediated by PPAR-gamma. The identification of such compounds makes possible the selective intervention in PPAR-gamma mediated pathways, without exerting inadvertent effects on pathways mediated by other PPAR isoforms.

References
Cell 1995 Dec 1;83(5):803-12.

Patent Status:
U.S. Patent No. 6,022,897 issued February 8, 2000
U.S. Patent No. 6,830,882 issued December 14, 2004

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S95031

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Multimeric Forms of Members of the Steroid/Thyroid Superfamily of Receptors with the Ultraspiracle Receptor (S95010.pdf)

Inventors
Ronald Mark Evans, Michael B. McKeown, Anthony Eugene Oro, William A. Segraves, Tso-Pang Yao

Applications
Gene Expression

In accordance with the present invention, it has been discovered that various members of the steroid/thyroid superfamily of receptors can interact with the insect-derived ultraspiracle receptor, to form multimeric species. Accordingly, the interaction of at least one member of the steroid/thyroid superfamily of receptors with at least the dimerization domain of the ultraspiracle receptor modulates the ability of said member of the steroid/thyroid superfamily of receptors to transactivate transcription of genes maintained under hormone expression control in the presence of the cognate ligand for said member of the superfamily.

References
Cell 71(1):63-72 (October 1992)

Patent Status:
U.S. Patent Number 6,281,330 issued August 28, 2001

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S95010

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Selective Modulation of Processes Mediated by Retinoid X Receptors, and Compounds Useful Therefor (Methoprene) (S94032.pdf)

Inventors
Ronald Mark Evans, David John Mangelsdorf, Richard Alan Heyman, Marcus F. Boehm, Margaret A. Harmon

Applications
Drug Discovery, Oncology

In accordance with the present invention, ligands have been discovered which selectively bind retinoid X receptors. Such ligands can be used for the selective modulation of RXR mediated processes. There are also provided pharmaceutical compositions comprising a pharmaceutically acceptable vehicle containing at least one of the above-described selective ligands. Such compositions are useful for the treatment of a variety of RXR mediated disease states, such as skin-related process (e.g., acne, aging, wrinkling, skin cancer, and the like) and cancers such as acute promyelocytic leukemia, testicular cancer, lung cancer, and the like. In vivo applications of the invention process may allow the modulation of various biological processes with reduced occurrence of undesirable side effects.

Patent Status:
U.S. Patent Number 5,990,163 issued November 23, 1999

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S94032

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Receptors: Their Identification, Characterization, Preparation and Use (S93001.pdf)

Inventors
Ronald Evans and Stanley Hollenberg

Applications
Drug Discovery and Development

Disclosed are novel hormone and hormone-like receptors wherein the trans-activation transcription domain(s) is modified in terms of position and/or copy number or otherwise versus parent receptor, such novel receptors having increased trans-activation transcription activation properties surprisingly superior to the parent receptor. Also disclosed are the recombinant methods and means for preparing such receptors and assays based upon the use of such receptors for screening and identifying putative materials that can affect such receptors and/or for the expression via induced transcription of a reporter or other desired, preferably heterologous gene or DNA product.

Patent Status:
U.S. Patent Number 5,310,662 issued May 10, 1994

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S93001

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Bioassays for Identifying Antagonists of Receptors of the Steroid/ Thyroid Superfamily (S91020.pdf)

Inventors
Ronald Evans and Stanley Hollenberg

Applications
Drug Discovery and Development

The present invention relates to bioassays for evaluating compounds as potential antagonists for members of the steroid hormone superfamily of receptor protein(s). The invention bioassay comprises culturing test cells expressing steroid receptor protein in the presence of increasing concentrations of at least one compound whose ability to inhibit the action of agonists on members of the steroid hormone superfamily of receptors is sought to be determined, and a fixed concentration of at least one agonist for said steroid hormone receptor protein(s). Test cells employed in the practice of the present invention contain DNA which expresses a member of the steroid hormone superfamily of receptor protein(s) in a form having improved trans activation transcription activity, relative to wild type receptor, and a DNA sequence comprising a response element for said hormone receptor protein operatively linked to a reporter gene. Improved trans activation transcription activity is provided by receptor having a plurality of at least one parental receptor trans activation domain selected from tau-1 or tau-2, located outside the DNA binding and ligand binding domains of the receptor protein. The invention assay is completed by monitoring the level of expression of reporter gene product as a function of the concentration of potential antagonist compound in the culture medium, thereby indicating the ability of potential antagonist compound(s) to inhibit activation of members of the steroid hormone superfamily of receptors.

Patent Status:
U.S. Patent Number 5,262,300 issued November 16, 1993

License Terms
Exclusive or Nonexclusive licenses available

Reference Number: S91020