Method of dopaminergic and serotonergic neuron formation from neuroprogenitor cells

• US 6,277,820 B1
• Filed: 04/09/1998
• Issued: 08/21/2001
• Est. Priority Date: 04/09/1998
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Ye, Weilan, Rosenthal, Arnon, Hynes, Mary A.
• Primary Examiner(s): Kunz, Gary L.
• Assistant Examiner(s): Gucker, Stephen
• Application Number:
  US09/057,860
• Time in Patent Office: 1,230 Days
• Field of Search: 514/2, 514/12
• US Class Current: 514/8.3
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: C12N 2501/119 Other fibroblast growth factors, e.g. FGF-4, FGF-8, FGF-10
• CPC Class Codes: C12N 2501/41 Hedgehog proteins; Cyclopamine (inhibitor)
• CPC Class Codes: C12N 5/0619 Neurons

Abstract

The present invention relates to neuronal formation and methods of treating diseases characterized by abnormalities in the activity of dopaminergic (DA) and serotonergic (5HT) neurons. In particular, the invention relates to a method of forming serotonergic neurons in vitro by contacting neuroprogenitor cells to an effective amount of native sequence, variants and functional fragments of FGF-4, FGF-8 and Shh. Additionally, disclosed is a method for forming dopaminergic neurons by contacting neuroprogenitor cells to an effective amount of FGF-8 and Shh. Further described are compositions, cell culture compositions and medical devices which contain sufficient amount of FGF-8, Shh or FGF-8, Shh and FGF-4 to stimulate differentiation into dopaminergic or serotonergic neurons, respectively. Further described are methods of using serotoneurgic neurons to treat disorders relating to food intake, hormone secretion, stress response, pain and immune function, sexual activity, cardiovascular function and temperature regulation, in particular, depression, proclivity to suicide, violent aggressive behavior, obsessive-compulsive behavior and anorexia/bulimia and schizophrenia. Further described are methods of using dopaminergic neurons to treat disorders relating postural reflexes, movement and reward-associated behaviors, specifically, Parkinson'"'"'s disease, schizophrenia and drug addiction. Further described is the coadministration of a neuronal survival factor, for example, NGF, CNTF, BDNF, NT-3, NT-4, aFGF, IL-1β, TNFα, IGF-1, IGF-2, TGF-β, TGF-β1 or skeletal muscle extract.

Claims

1. A method of forming dopaminergic neurons by contacting in vitro neuroprogenitor cells with an effective amount of FGF-8 and sonic hedgehog (Shh) polypeptide wherein said FGF-8 and Shh polypeptides are encoded by nucleic acid sequences encoding polypeptides comprising SEQ ID NO:

4 and SEQ ID NO;

6, respectively.

3. The method of claim 1 wherein the FGF-8 and Shh polypeptides are in the form of a composition further comprising a pharmaceutically-acceptable carrier.

2. A composition comprising a pharmaceutically-acceptable carrier and an effective amount of the FGF-8 polypeptide of SEQ ID NO:

4 and the Shh polypeptide of SEQ ID NO;

6 to stimulate differentiation of neuroprogenitor cells into dopaminergic neurons.