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A Molecular Switch Regulating Neurogenesis (S04010.pdf)

Inventors
Fred Gage and Tomoko Kuwabara

Applications
CNS, Modulation of Gene Expression
A "master switch" that determines whether the genetic program that mediates neural differentiation is repressed or activated

During the initiation of neurogenesis, neural stem cells exit the undifferentiated state and commit to becoming neuroblasts, the first stage in the differentiation toward neurons. Previous efforts have been unsuccessful in revealing the mechanism which controls this neural phenotype development. This invention describes the transcriptional regulatory mechanism that functions as a "master switch" in neural development, determining whether the genetic program that mediates neural differentiation is repressed or activated. The mechanism relates to recently identified LEF/Sox overlapping response elements within the upstream regulatory sequences of neural specific genes such as NeuroD1. Activation via this molecular switch induces neurogenesis in neural stem cells and controls the irreversible commitment step from stem cells to neuroblasts. Compositions and methods are described for directing neural specific expression of polynucleotide sequences. These can be used to modulate differentiation of stem cells into neural lineage cells, or, for the prevention/inhibition of differentiation-for example, to maintain a stem cell in an undifferentiated state. New screening methods have also been identified that are particularly suited for high-throughput evaluation of large composition libraries to identify agents that modulate differentiation of stem cells..

References
No publications to date

Patent Status:
Application pending

License Terms:
Exclusive, Partially Exclusive, Nonexclusive license negotiable

Reference_Number: S04010
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Regulation of Tyrosine Hydroxylase Expression (S98035.pdf)

Inventors
Kazuhiro Sakurada, Theo Palmer and Fred H. Gage

Applications
Gene Expression, CNS
Nurr1 polypeptide upregulates tyrosine hydroxylase activity and promotes expression of DOPA, norepinenephrine and epinephrine.

The invention describes methods to regulate tyrosine hydroxylase expression and the treatment of catecholamine-related diseases including Parkinson's disease, manic depression and schizophrenia. The basis for the invention is the discovery that expression of Nurr1 polypeptide induces tyrosine hydroxylase in both undifferentiated and differentiated mammalian cells including adult hippocampal progenitor cells. Specifically, the invention provides cells that contain exogenous nucleic acid as well as methods and materials for inducing tyrosine hydroxylase expression, treating catecholamine-related deficiencies and identifying tyrosine hydroxylase-related deficiencies. Neural progenitor cells, neural cells and neural stem cells which contain the exogenous nucleic acid and express the Nurr1 polypeptide are upregulated for tyrosine hydroxylase activity and thus promote the expression of DOPA, norepinephrine and epinephrine. These cells can be used to treat catecholamine deficiency diseases directly. In addition, these diseases can be treated by transfection using the genetic construct for Nurr1 expression..

References
Development. 126(18): 4017-26 (Sept. 1999)

Patent Status:

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IsK Knockout Mouse (ISK.pdf)

Inventors
Steve Heinemann

Applications
Molecular Neurobiology, CNS, Drug Discovery and Development
Mouse model for waltzer syndrome exhibiting hyperactivity, head tilt and bobbing

The IsK gene encodes a small protein of 129-130 amino acids that spans the cell membrane only once and gives rise to slowly activating, voltage dependent K+ conductances. The IsK gene is expressed in the kidney, heart and inner ear. Gene targeting techniques were used in mouse embryonic stem cells to produce mice with a null mutation of the IsK gene. A standard replacement vector was created and used to delete the entire coding sequence of the IsK gene. These IsK knockout mice, which express aberrant behavior due to the K+ channel defect, are models for the waltzer syndrome exhibiting hyperactivity, bi-directional circling, head tilt and bobbing..

References
Workshop on Inner Ear Biology, August 31 - September 3, 1996, Utrecht, The Netherlands
Nature 384: News and Views (1996)
J. Membr. Biol. 146: 283-291 (1995) and 147: 263-273 (1995)
Neuron 17: 1251-1264 (1996)

Patent Status:
No Application filed

License Terms:
Nonexclusive license negotiable

Reference_Number: ISK
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Kainate Receptor Subunit GluR7 Polymorphisms for Diagnosing Predisposition and for Therapy of Mood Disorders (S00007.pdf)

Inventors
Hans Schiffer and Stephen Heinemann

Applications
CNS, Mood Disorders, Diagnostic, Therapeutic, Drug Discovery
The Kainate Receptor Subunit GluR7 Gene is Associated with Mood Disorders

Mood disorders rank among the top ten causes of disability worldwide. Despite intensive research efforts, the specific genes involved in mood disorder pathology remain to be identified. Thus, it would be useful to identify the genes involved in mood disorders so as to improve diagnosis and therapy. The invention includes methods for determining the predisposition of a subject to a mood disorder by determining the presence of a kainate receptor subunit GluR7 allelic genotype or allelic phenotype. The invention also includes a method of treating or preventing a mood disorder and methods for identifying a compound useful for treatment. Transgenic non-human animals that express only a particular human GluR7 allele also are provided as a model of a human mood disorder..

References
The Journal of Neuroscience 20(24):9025-9033 (December 2000)

Patent Status:

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Nerve Regeneration: Compositions and Methods (S05002.pdf)

Inventors
Sun Tsung-Chang and Kuo-Fen Lee

Applications
CNS, Nerve Growth and Regeneration
Methods and compositions for promoting nerve growth and/or regeneration, including what is believed to be the first demonstration of locomotor functional recovery following a complete spinal cord transection.

The central nervous system (CNS) has a limited capability to repair itself, to a large extent because regeneration is impeded by various nerve outgrowth inhibitors. Compositions and methods that suppress these inhibitory mechanisms, and/or enhance neurotrophic mechanisms, are needed to overcome, at least in part, the limited ability of the CNS to recover from injury. This invention demonstrates that the protein p45 promotes rapid regeneration of nerves of the CNS, most dramatically illustrated by corticospinal tract (CST) nerve regeneration in a living adult p45-overexpressing transgenic mouse subject following a complete spinal cord transection. This remarkable discovery, as well as mapping of p45 functional regions, enables compositions and in vivo and in vitro methods for promoting nerve growth and/or regeneration. It has also been determined that this is accomplished, at least in part, via a protein-protein interaction with p75. This discovery makes possible methods of screening for agents that affect the p45-p75 complex and thereby have the potential to promote regrowth of neurites, axons, and nerves. The invention also describes pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an isolated polypeptide..

References
No publications to date

Patent Status:
Application pending

License Terms:
Exclusive, Partially Exclusive, Nonexclusive license negotiable

Reference_Number: S05002
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Corticotropin-Releasing Factor (CRF) Antagonists (S96032.pdf)

Inventors
Jean Rivier and Wylie Vale

Applications
CNS, GI, Drug Discovery and Development
Drugs to activate CRF receptors based on peptide antagonists

The inventions relate to antagonists of the CRF hentetracontapeptides, as well as to members of the larger family of CRF-like peptides, to pharmaceutical compositions containing such CRF antagonists, and to methods of treating mammals using such CRF antagonists. CRF antagonists may be used to treat anxiety, depression, irritable bowel syndrome, immune suppression, Alzheimer's disease, hemorrhagic stress, drug addiction and withdrawal symptoms, and fertility problems. In addition, such CRF antagonists can provide the basis for valuable methods for drug screening in order to detect even more potent molecules that will bind to and/or activate CRF receptors..

References
Brain Research 744:166-170 (1997)
J. Med. Chem. 41: 5002-5011 (1998)
J. Med. Chem. 41: 5012-5019 (1998)
J. Med. Chem. 42: 2175-3182 (1999)
J. Pharm. Exp. Ther. 290(2): 629-634 (1999)

Patent Status:
U.S. Patent No. 5,109,111 issued 4/28/92
U.S. Patent No. 5,510,458 issued 4/23/96
U.S. Patent No. 5,874,227 issued 2/23/99

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Melanin-Concentrating Hormones (S48600.pdf)

Inventors
Joan Vaughan, Wolfgang Fischer, Jean Rivier, Jean-Louis Nahon, Francoise Presse, Wylie Vale

Applications
CNS, Oncology, Drug Discovery and Development
MCH as a therapeutic for suppression of melanoma-proliferation by topical application of melanin-concentrating hormones, or as a target for molecules acting on MCH

The invention relates to mammalian melanin-concentrating hormone (MCH), MCH precursors (NEI and NGE) and DNA encoding same. Mammalian MCH is useful to treat humans and other mammals to lighten skin color, by local or topical application. It is also useful to suppress the proliferation of certain skin tumor cells, such as melanomas, when suitably applied by topical application or the like. It is also found that mammalian MCH can be used to modulate the secretion of ACTH in humans and other mammals and thus can be used to modify the effects of stress, by systemically administering an effective amount of mammalian MCH..

References
Endocrinology 125: 1660-1665 (1989) and 130: 1024-1029 (1992)
Neuroscience Lett. 136: 145-149 (1992)

Patent Status:
U.S. Patent No. 5,449,766 issued September 12, 1995 (S55511)

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Kir Channel Modulators (S06017.pdf)

Inventors
Scott Pegan, Paul Slesinger, Senyon Choe, Prafulla Aryal

Applications
Cardiology, CNS, Screening, Drug Discovery
Methods and materials for modulating Kir channel activity and identification of related compounds.

Inwardly-rectifying potassium (Kir) channel proteins are involved in a diverse range of biological processes, including regulation of cardiac and neurological functions. In contrast to voltage-gated potassium channels that allow large fluxes of K+ ions out of the cell when opened during membrane electrical activity, Kir channels allow fluxes of K+ ions out of the cell at resting membrane potentials, maintaining excitability. In addition, Kir channels are modulated by alcohols. Aberrant activity of Kir channels has been linked to a variety of endocrine, cardiac, and neurological disorders. In particular, mutations in Kir channel proteins have been implicated in analgesia, cardiac arrhythmias and Andersen's Syndrome. Consequently, new compounds discovered using the methods described could be therapeutically useful to control heart dysfunctions and neurological disorders such as epilepsy, as well as for developing novel analgesics. Scientists at the Salk Institute have recently determined the structure of the cytoplasmic domain of the Kir2 channel protein, and discovered that a small alcohol-like molecule, known as MPD, binds to a specific location within the protein domain. Additional studies indicate that low concentrations of MPD activate the related Kir3 subfamily of channel proteins. The Kir channel three-dimensional structure has been used to design mutants for characterizing the pharmacological properties of the alcohol pocket. This discovery provides a stereochemical basis for the systematic design, synthesis, and screening of related alcohol-like compounds in order to identify those that modulate Kir channel activities. The technology disclosed in the pending patent includes the elucidated structure of a representative Kir channel protein in combination with an alcohol and methods for identifying agents that modulate Kir channel activity and predicting whether an agent is capable of binding to a Kir channel..

References
Biochemistry. 46: 5315-5322 (2007)

Patent Status:
U.S. Patent Application filed 6/20/2007

License Terms:
Exclusive and Non-Exclusive Licenses available

Reference_Number: S06017
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Corticotropin Releasing Factor-Binding Protein (CRF-BP) (S54426.pdf)

Inventors
Wylie Vale, Ellen Potter, Dominic Behan, Wolfgang Fischer, Elizabeth Linton, and Philip Lowry

Applications
CNS, Cardiovascular, Oncology, Obesity, Drug Discovery and Development
Proteins capable of binding and modulating the biological effect of CRF

The invention relates to CRF-BPs which are capable of binding to and modulating the biological effect of CRF and which have therapeutic applications. These CRF-BPs can be administered therapeutically to bind to and inactivate CRF thereby reducing high ACTH levels in mammals caused by excess CRF and can be used to treat Cushing's Disease, and the like. These CRF-BPs are also useful in combating pituitary tumors that produce CRF. Moreover, they can be used to reduce pituitary ACTH secretion and hence reduce cortisol levels under any condition in which they are abnormally high, such as during chronic stress or in patients afflicted with anorexia nervosa or alcoholism. CRF-BP or fragments thereof and/or antibodies to the proteins may be employed in diagnostic assays to determine the levels of CRF, CRF-BP and the ratio of CRF/CRF-BP in a vascular fluid sample. The DNA or subsequence thereof can be used as probes for genetic material in certain assays. The anti-CRF-BP antibodies are also useful to purify the CRF-BP protein and to modulate the biological effect of the CRF-BPs proteins. CRF-BPs can also be employed to screen for inhibitors which may be used to treat obesity and Alzheimer's disease..

References
Nature 349:423-426 (January 1991)
Genomics 16:63-68 (1993)

Patent Status:
U.S. Patent No. 5,733,790 issued March 31, 1998
U.S. Patent No. 5,910,428 issued June 8, 1999
Numerous Foreigns

License Terms:
Exclusive, Partially Exclusive, Nonexclusive license negotiable

Reference_Number: S54426
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Corticotropin-Releasing Factor Overproducing Transgenic Mice (S93011.pdf)

Inventors
Wylie Vale, Mary Stenzel-Poore, George Koob, Stephen Heinrichs

Applications
CNS, Drug Discovery and Development
Transgenic mouse useful to screen compounds that modulate corticotropin-releasing factor levels

This invention relates to a transgenic mouse model exhibiting chronic CRF hypersecretion. These animals express high levels of ACTH and corticosterone throughout their life span and develop phenotypic changes consistent with Cushing's disease and anxiety due to excess glucocorticoid production. Consequently, the invention transgenic mice are useful for a variety of applications, e.g., to screen for compounds that can modulate in-vivo CRF levels, and the like..

References
Endocrinology 130: 3378-3386 (1992)
J. Neuroscience 14: 2579-2584 (1993)

Patent Status:
U.S. Patent No. 6,166,287 issued December 20, 2000

License Terms:
Nonexclusive license negotiable

Reference_Number: S93011
Contact: Mike White, Ph.D., CLP o Director, OTM o 858.453.4100 x1703 o mwhite@salk.edu

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Urocortin (S96012.pdf)

Inventors
Wylie Vale, Joan Vaughan, Cynthia Donaldson, Kathy Lewis, Paul Sawchenko, Jean Rivier, Marilyn Perrin

Applications
CNS, Cardiovascular
A native mammalian peptide with potent hypotensive activity used as a therapeutic or target

The invention relates to Urocortin, a native mammalian peptide generally related to Urotensin I and Corticotropin Releasing Factor (CRF). Urocortin or analogs thereof not only are potent hypotensive agents but they have additional pharmacological and physiological properties over and beyond those of heretofore known CRFs. Pharmaceutical compositions of Urocortin can be used to lower blood pressure or increase coronary flow, decrease swelling and inflammation, improve memory and learning performance, and elevate mood. The invention also relates to competitive binding assays which are particularly useful for screening candidates for new drugs..

References
Nature 378: 287-292 (1995)
Endocrinology 137: 2167-2170 (1996)
Science 273: 1561-1564 (1996)

Patent Status:

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New Tumor Mouse Models Using Lentiviral Vectors (S07006B.pdf)

Inventors
Tomotoshi Marumoto, Inder Mohan Verma, Yasushi Soda, Yifeng Xia

Applications
Oncology, CNS, Transgenic Animals
Methods, compositions and systems for modeling tumorigenesis and generating tumor cells that are representative of human tumors in model animals.

Incidence rates of primary CNS lymphoma in patients over age 60 have increased nearly 10-fold in the past two decades, and a form of primitive neuroectodermal tumor is the most frequent CNS tumor in children. Regardless of treatment, the prognosis of these and similar brain tumors is dismal. Primary reasons for the lack of therapeutic advances include insufficient knowledge about lymphomagenesis, the identity of the appropriate tumor cells to target, and the absence of good animal models. Current tumor models typically employ a shotgun approach that generates random or unrepresentative tumors, or manipulates every cell, causing them to undergo tumorigenesis en masse. Most of these model systems have been used for drug testing and for studying molecular mechanisms of oncogenesis. Unfortunately, because they are also based on the activation of oncogenes or inactivation of suppressors in the immature cells of the fetus or neonatal mice, most do not faithfully mimic human tumors in adults. In order to recapitulate what actually happens in the tumor in humans, it is necessary to induce oncogenic events in adult mice in a cell-type-specific manner. For example, tumors more typically initiate by activating oncogenes or inactivating suppressor genes in single cells, then progress to a malignant phenotype by accumulation of additional mutations. Furthermore, current models do not take into account the role of the normal cells surrounding a mutated cell in tumor progression. Scientists at the Salk Institute have developed a novel way to induce oncogenic event(s) in adult mice in a cell-type-specific manner using lentiviral vectors that are able to infect non-dividing cells in most organs in adult mice. In proof-of-principle experiments, an animal model intra-cranially transplanted with patients' lymphoma cells is the first to reproduce the necessary microenvironment for the generation of primary CNS lymphomas. The resulting tumor cells showed very similar histological characteristics to human glioblastomas, were able to survive in culture, and formed neurosphere-like structures. As few as 100 cells could regenerate a robust glioma, indicating the presence of tumor stem/initiating cells that could be the target of therapy. Similar technology can be applied to any organ, such as pancreas, breast, and prostate, and tumor models based on this approach could be excellent candidates to use for drug screening. .

References
None to date

Patent Status:
U.S. Patent Filed 3/5/2007

License Terms:
Non-Exclusive Licenses available by field of use

Reference_Number: S07006B
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu

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Regression Based Exon Array Protocol System and Applications (S07011.pdf)

Inventors
Gene W. Yeo, Fred H. Gage

Applications
Exon Array Analysis, Stem Cells, CNS
A novel computational method, Regression-based Exon Array Protocol (REAP) is based on robust regression analysis of signal estimates from an exon array but can also be applied to similarly structured datasets especially from the high-throughput sequencing field. REAP can be used to identify alternative RNA splicing events that distinguish pluripotent embryonic stem cells from multipotent neural progenitors, but can generally be applied to identify new events given any cell-types.

Pre-mRNA splicing is a critical step by which the genetic information of higher Eukaryotes encodes for the full spectrum of expressed proteins. Once a pre-mRNA is transcribed it undergoes the highly regulated process of splicing, consisting of the removal of intronic regions and sequential joining of exonic regions, which results in the production of mature mRNA transcript that will specify the synthesis of a particular protein isoform. Although most exons are constitutively spliced, meaning that the exon is always recognized and spliced in an identical manner, it has recently become clear that up to 70% of genes contain alternatively spliced exons, in which there is variable recognition of exon-intron boundaries in a tissue-, condition-, developmental stage specific- or disease-specific manner. The availability of Affymetrixª exon arrays provides the means to analyze the expression of every known and predicted exon in the human genome, but there is a lack of successful algorithms for data analysis. Salk scientists have created a novel computational method called REAP (Regression-based Exon Array Protocol), to analyze exon array data. For example, REAP's robust regression technique has been used by the inventors to analyze signal estimates from the data to identify alternatively spliced exons. Human embryonic stem cells (hESC) are pluripotent cells that can propagate as undifferentiated, or differentiate into numerous cell types. Deriving neural progenitors (NP) from hESC is the first step in creating homogeneous populations of cells that will differentiate into the myriad neuronal subtypes necessary to form a human brain. The alternative exons thus identified are novel, and are specific to ESC, making it possible to characterize alternative RNA splicing events that distinguish pluripotent embryonic stem cells from multipotent neural progenitors. REAP candidate alternative exons are consistent with other methods for discovering alternate exons, and are also enriched in genes encoding serine/theronine kinases (SRK) and helicase activities. An example is the alternative exon in the SLK gene that is included in hESC, but excluded in NP as well as in other differentiated tissues. Moreover, by comparing genomic sequences across multiple mammals, dozens of conserved candidate binding sites were identified that were enriched proximal to REAP candidate exons. The REAP algorithm can be implemented as software for analyzing data from Affymetrixª exon arrays, or any data of similar structure, such as high-throughput sequencing data..

References
PLoS Computational Biology, 3(10), e196 (October 2007)

Patent Status:
U.S. Application Filed 8/21/2007

License Terms:
Exclusive and Non-Exclusive Licenses Available

Reference_Number: S07011
Contact: Dave Odelson, Ph.D. o Senior Licensing Executive o 858.453.4100 x1223 o dodelson@salk.edu