The General Hospital Corporation

Massachusetts Eye and Ear Infirmary

Biogen, Incorporated

Duke University

University of Massachusetts

Massachusetts General Hospital Corporation

Patricia K Donahoe

David T MacLaughlin

David Pepin

Gerald P Budzik

David A Swann

Jose Teixeira

Joseph P Vacanti

Demetrios Vavvas

Richard L Cate

Meredith Mudgett-Hunter

Peter T Masiakos

Mien Van Hoang

Richard C Ragin

Michael Gustafson

Guangping Gao

Robert H Brown, Jr

Wei-Wu He

Tongwen Wang

Xiao-Fan Wang

Paul P Szotek

Eric Fynn-Thompson

Frederic Preffer

Elizabeth A Catlin

Rafael Pieretti-Vanmarcke

David T MacLaughkin

David Michael Dombkowski

Wei W He

Edward M Barksdale

James Epstein

Robert L Parry

Tai Wai Chin

David T Maclaughlin

One aspect of the invention provides a method of contraception by administering to a female subject a composition comprising Mullerian inhibiting substance (MIS). The MIS can be produced endogenously in the subject by a vector, where the vector comprises a polynucletide encoding a recombinant MIS protein. In some embodiments, the contraception is permanent and only requires administration of the composition once. Another aspect of the invention relates to a method of preserving an ovarian reserve, the method comprising administering to a female subject a composition comprising MIS or an inducible vector that comprises a polynucleotide encoding a recombinant MIS protein.

Use of Mullerian inhibiting substance (MIS) proteins for contraception and ovarian reserve preservation

One aspect of the invention provides a method of ovarian protection by administering to a female subject a composition comprising Mullerian inhibiting substance (MIS). Ovarian protection can be an induced arrest of folliculogenesis to preserve fertility. In some embodiments, ovarian protection is oncoprotection, the protection of the ovarian function during a cytotoxic treatment, e.g., chemotherapy. Another aspect of the invention relates to a method of treating PCOS, the method comprising administering to a female subject a composition comprising recombinant MIS protein.

Mullerian inhibiting substance (MIS) proteins for ovarian and uterine oncoprotection, and ovarian reserve and uterine preservation

One aspect of the invention provides a method of contraception by administering to a female subject a composition comprising Mullerian inhibiting substance (MIS). The MIS can be produced endogenously in the subject by a vector, where the vector comprises a polynucleotide encoding a recombinant MIS protein. In some embodiments, the contraception is permanent and only requires administration of the composition once. Another aspect of the invention relates to a method of preserving an ovarian reserve, the method comprising administering to a female subject a composition comprising MIS or an inducible vector that comprises a polynucleotide encoding a recombinant MIS protein.

Use of mullerian inhibiting substance (MIS) proteins for contraception and ovarian reserve preservation

The present invention relates to modified recombinant human MIS protein which has improved cleavage and increased bioactivity and increased potency as compared to wild-type human MIS protein. Other aspects of the invention relate to methods to prevent and treat cancers, such as cancers that express the MIS receptor type II (MISRII) by administering to a subject a composition comprising a recombinant human MIS protein. Another aspect of the present invention relates to methods to lower plasma androgen levels in a subject, and/or for the treatment of a subject with a disease characterized by excess androgen. Another aspect provides pharmaceutical compositions and kits and methods for use comprising a recombinant human MIS protein. Another aspect of the present invention relates to methods to decrease the dose of a chemotherapeutic agent by administering the chemotherapeutic agent with the recombinant MIS protein that lowers the effective dose of the chemotherapeutic agent.

Modified Mullerian inhibiting substance (MIS) proteins and uses thereof for the treatment of diseases

The present invention relates to methods to treat a neurodegenerative disease or disorder, e.g., a motor neuron disease in a subject, whereby the subject is administered a recombinant human Mullerian Inhibiting Substance (MIS) protein as disclosed herein, wherein the recombinant human MIS protein comprises a modified Kex cleavage site for increased cleavage. The recombinant human MIS protein can be produced from a pre-proprotein comprising a non-MIS leader sequence or a functional fragment thereof in place of the MIS leader sequence.

Viral vectors for expressing a modified mullerian inhibiting substance (MIS) protein

The present invention generally relates to methods, assays, compositions and kits related to a subpopulation of ovarian cancer stem cells which are selected or enriched by chemotherapeutic agents and inhibited by MIS (Mullerian Inhibiting Substance) and MIS mimetics. In particular, the present invention relates to a population of CD44+/CD24+/EpCam+/ECad&#x2212; subpopulation of ovarian cancer stem cells. The present invention also provides methods to screen a subject with ovarian cancer to identify if they have an ovarian cancer comprising CD44+/CD24+/EpCam+/ECad&#x2212; ovarian cancer stem cells, and methods to identify and enrich or isolate for such ovarian cancer cell populations.

Ovarian cancer stem cells and methods of isolation and uses thereof

The present invention relates to compositions and methods for treating, characterizing and diagnosing ovarian cancer. In particular, the present invention provides methods for treating and/or preventing ovarian cancer in a subject by administering to the subject an effective amount of Mullerian Inhibiting substance and/or an effective amount of an agent that inhibits BCRP1. The present invention further provides methods to identify and/or enrich for populations of ovarian cancer stem cells and populations of somatic ovarian stem cells, in particular, enrichment for populations of coelomic somatic ovarian stem cells, subcoelomic/stromal somatic ovarian stem cells and periphilar medullary somatic ovarian stem cells. The present invention also provides somatic ovarian stem cell markers and ovarian cancer stem cell markers, as well as methods to identify agents which selectively inhibit the proliferation of ovarian cancer stem cells as compared to somatic ovarian stem cells.

Collecting ovarian cancer stem cells from ovarian cancer cells

Provided herein are pyrazoloanthrones or functional derivatives or analogs thereof to activate MIS receptor-mediated downstream effects in a cell. In particular, methods are provided to prevent and treat cancer that expresses MIS receptor type II (MISRII) by administering to a subject at least one pyrazoloanthrone or a functional derivative or analog thereof. Also provided herein are methods to lower plasma androgen levels in a subject, and/or for the treatment of a subject with a disease characterized by excess androgen, whereby the subject is administered at least one pyrazoloanthrone or a functional derivative or analog thereof. Also provided are methods to decrease the dose of a chemotherapeutic agent by administering the chemotherapeutic agent with a pyrazoloanthrone or a functional derivative or analog thereof that lowers the effective dose of the chemotherapeutic agent.

Pyrazoloanthrone and derivatives thereof for the treatment of cancers expressing MISRII

Normal cells, such as fibroblasts or other tissue or organ cell types, are genetically engineered to express biologically active, therapeutic agents, such as proteins that are normally produced in small amounts, for example, MIS, or other members of the TGF-beta family Herceptin&#x2122;, interferons, and anti-angiogenic factors. These cells are seeded into a matrix for implantation into the patient to be treated. Cells may also be engineered to include a lethal gene, so that implanted cells can be destroyed once treatment is completed. Cells can be implanted in a variety of different matrices. In a preferred embodiment, these matrices are implantable and biodegradable over a period of time equal to or less than the expected period of treatment, when cells engraft to form a functional tissue producing the desired biologically active agent. Implantation may be ectopic or in some cases orthotopic. Representative cell types include tissue specific cells, progenitor cells, and stem cells. Matrices can be formed of synthetic or natural materials, by chemical coupling at the time of implantation, using standard techniques for formation of fibrous matrices from polymeric fibers, and using micromachining or microfabrication techniques. These devices and strategies are used as delivery systems via standard or minimally invasive implantation techniques for any number of parenterally deliverable recombinant proteins, particularly those that are difficult to produce in large amounts and/or active forms using conventional methods of purification, for the treatment of a variety of conditions.

Delivery of therapeutic biologicals from implantable tissue matrices

Normal cells, such as fibroblasts or other tissue or organ cell types, are genetically engineered to express biologically active, therapeutic agents, such as proteins that are normally produced in small amounts, for example, MIS, or other members of the TGF-beta family Herceptin&trade;, interferons, andanti-angiogenic factors. These cells are seeded into a matrix for implantation into the patient to be treated. Cells may also be engineered to include a lethal gene, so that implanted cells can be destroyed once treatment is completed. Cells can be implanted in a variety of different matrices. In a preferred embodiment, these matrices are implantable and biodegradable over a period of time equal to or less than the expected period of treatment, when cells engraft to form a functional tissue producing the desired biologically active agent. Implantation may be ectopic or in some cases orthotopic. Representative cell types include tissue specific cells, progenitor cells, and stem cells. Matrices can be formed of synthetic or natural materials, by chemical coupling at the time of implantation, using standard techniques for formation of fibrous matrices from polymeric fibers, and using micromachining or microfabrication techniques. These devices and strategies are used as delivery systems via standard or minimally invasive implantation techniques for any number of parenterally deliverable recombinant proteins, particularly those that are difficult to produce in large amounts and/or active forms using conventional methods of purification, for the treatment of a variety of conditions that produce abnormal growth, including treatment of malignant and benign neoplasias, vascular malformations (hemangiomas), inflammatory conditions, keloid formation, abdominal or plural adhesions, endometriosis, congenital or endocrine abnormalities, and other conditions that can produce abnormal growth such as infection. Efficacy of treatment with the therapeutic biologicals is detected by determining specific criteria, for example, cessation of cell proliferation, regression of abnormal tissue, or cell death, or expression of genes or proteins reflecting the above.

The present invention provides a method of treating a condition or disease characterized by an excess of one or more androgens, the method comprising administering an effective amount of MIS protein or nucleic acid encoding MIS to a patient. The present invention also provides a method of decreasing the level of one or more androgens to a level below the normal level, the method comprising administering an effective amount of MIS protein or nucleic acid encoding MIS to a patient. The methods of the present invention are particularly well-suited for the treatment of prostatic cancer, polycystic ovarian disease, benign prostatic hypertrophy, and precocious puberty.

Use of Mullerian inhibiting substance for treating excess androgen states

The present invention concerns the TGF-.beta. receptor-mediated signaling pathway. The invention is based on the unexpected finding that TGF-.beta. receptor-mediated signaling is inhibited by the cytoplasmic interactor FKBP12. The invention further concerns methods and pharmaceutical compositions for enhancing cellular response to TGF-.beta. ligands. A screening assay is also provided for identifying macrolide potentiators capable of binding FKBP12 and thereby blocking FKBP12-inhibition of TGF-.beta. receptor-mediated signaling.

Methods and compositions for enhancing cellular response to TGF-.beta.

This application concerns the treatment of certain tumors using an effective amount of the glycoprotein Mullerian Inhibiting Substance (MIS). This application further concerns the treatment of certain tumors using an effective amount of the C-terminal fragment of MIS. Also, this application concerns DNA sequences encoding the C-terminal fragment of MIS, vectors containing the DNA sequence and transformed host cells capable of producing the C-terminal fragment. This application further concerns treating certain tumors by transfecting tumor cells with a gene coding for MIS or the C-terminal fragment of MIS. Gene therapy treatments for inhibiting growth of certain tumors are also provided. Further, this application concerns a method for modulating class I histocompatibility antigens with MIS and EGF.

Use of mullerian inhibiting substance for treating certain tumors and

Isolated DNAs (e.g., cDNAs or genomic fragments) encoding MIS receptors, inhibin receptors, bone morphogenic protein receptors, or other novel members of the TGF-.beta. family of receptors, or soluble, ligand-binding fragments thereof; vectors or cells which contain such DNAs; and substantially pure polypeptides encoded by such DNAs, whether produced by expression of the isolated DNAs, by isolation from natural sources, or by chemical synthesis.

DNA encoding a receptor for Mullerian inhibitory substance, misr1, and

Isolated DNAs (e.g., cDNAs or genomic fragments) encoding TGF-.beta. type I receptors, or soluble, ligand-binding fragments thereof; vectors or cells which contain such DNAs; and substantially pure polypeptides encoded by such DNAs, whether produced by expression of the isolated DNAs, by isolation from natural sources, or by chemical synthesis.

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Boston, MA, United States of America

Patricia K Donahoe