Regeneron Pharmaceuticals, Inc.

Yale University

Max-planck-gesellschaft Zur F&#xf6;rderung Der Wissenschaften E. V.

Ronald M Lindsay

George D Yancopoulos

Joachim Leibrock

Mark E Furth

Stephen P Squinto

Eric M Shooter

Ulrich Suter

Hans F Thoenen

Stanley J Wiegand

Nikos Panayotatos

Friedrich Lottspeich

Nancy Y Ip

Peter C Maisonpierre

Hans Thoenen

Yves-Alain Barde

David Edgar

Judith Siuciak

Eric J Nestler

David S Russell

Dana Beitner-Johnson

Melissa T Berhow

Keith D Anderson

Nancy P Ip

Andreas Hohn

Charles A Altar

Ralph Alderson

Carolyn Hyman

Magdalena Hofer

Dan Lindholm

Francisco Zafra

Karen Bailey

The present invention relates to neurotrophin-3 (NT-3), a newly discovered member of the BDNF gene family. It is based, in part, on the identification of regions of nucleic acid sequence homology shared by BDNF and NGF (U.S. patent application Ser. No. 07/400,591, filed Aug. 30, 1989, incorporated by reference herein). According to the present invention, these regions of homology may be used to identify new members of the BDNF/NGF gene family; such methodology was used to identify NT-3. The present invention provides for the genes and gene products of new BDNF/NGF related neurotrophic factors identified by these methods. According to the invention, NT-3 may be used in the diagnosis and/or treatment of neurologic disorders, including, but not limited to, Alzheimer's disease and Parkinson's disease. Because NT-3 has been observed to exhibit a spectrum of activity different from the spcificities of BDNF or NGF, NT-3 provides new and valuable options for enducing regrowth and repair in the central nervous system.

Methods of treating peripheral neuropathies using neurotrophin-3

Modified ciliary neurotrophic factors and methods for their production and therapeutic use, especially in the treatment of Huntington's disease.

Administration modified ciliary neurotrophic factors

Infusions of brain-derived neurotrophic factor, neurotrophin-3 or neurotrophin-4 are used to produce analgesia in mammals. In addition, these neurotrophins are used to treat other diseases or disorders mediated by serotonin.

Method of producing analgesia using neurotrophins

The present invention is broadly directed to treatment of an addictive disease or disorder. In particular, the invention relates to inhibiting or reversing the biochemical and neurophysiological changes that correlate with behavioral changes of addictive diseases or disorders. The method of the invention comprises administering to a subject suspected of suffering from an addictive disease or disorder an amount of brain-derived factor (BDNF) or neurotrophin-4 (NT-4), or both, effective to reverse behavioral changes that are associated with the addictive disease or disorder. In a specific Example, administration of BDNF or NT-4 inhibits or reverses increased expression of tyrosine hydroxylase and glial ibrillary acidic protein in the ventral tegmental area of the brain, and inhibits or reverses increased levels of cyclic-AMP-dependent protein kinase activity in the nucleus accumbens.

Methods for treating addictive disorders

The present invention relates to chimeric neurotrophic factors which comprise at least a portion of a naturally occurring cellular factor and a portion of at least one other molecule such that the resulting chimeric molecule has neurotrophic activity. It is based, in part, on the discovery that chimeric molecules comprising portions of both NGF and BDNF are likely to possess neurotrotrophic activity, and in some cases exhibit a spectrum of activity larger than that of either parent molecule. It is further based on the discovery that chimeric molecules comprising neurotrophic factor sequences as well as additional peptide sequences may retain neurotrophic activity, and in some cases may exhibit a more potent activity than the parent factor. The chimeric neurotrophic factor molecules of the invention provide a number of advantages relative to naturally occurring neurotrophic factors. Chimeric neurotrophic factors may be used to provide, for example, the activity of two neurotrophic factors in a single molecule, or may serve as superagonists of an endogenous neurotrophic factor, thereby enabling an increased biological response at lower doses.

Multitrophic and multifunctional chimeric neurotrophic factors

The present invention relates to chimeric neurotrophic factors which comprise at least a portion of a naturally occurring cellular factor and a portion of at least one other molecule such that the resulting chimeric molecule has neurotrophic activity. It is based, in part, on the discovery that chimeric molecules comprising portions of both NGF and BDNF are likely to possess neurotrotrophic activity, and in some cases exhibit a spectrum of activity larger than that of either parent molecule. It is further based on the discovery that chimeric molecules comprising neurotrophic factor sequences as well as additional peptide sequences may retain neurotrophic activity, and in some cases may exhibit a more potent activity than the parent factor. The chimeric neurotrophic factor molecules of the invention provide a number of advantages relative to naturally occurring neurotrophic factors. Chimeric neurotrophic factors may be used to provide, for example, the activity of two neurotrophic factors in a single molecule, or may serve as superagonists of an endogenous neurotrophic factor, thereby enabling an increased biological response at lower doses. Nucleic acids and plasmids encoding the chimeras are disclosed.

Multitrophic and multifunctional chimeric neurotrophic factors, and

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Briarcliff Manor, NY, United States of America

Ronald M Lindsay