Identifying and Modulating Molecular Pathways that Mediate Nervous System Plasticity

• US 20090297573A1
• Filed: 04/12/2007
• Published: 12/03/2009
• Est. Priority Date: 04/14/2006
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Kreiman, Gabriel, Tropea, Daniela, Sur, Mriganka
• Granted Patent: US 8,969,295 B2
• Time in Patent Office: Days
• US Class Current: 424/422
• 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 38/217 IFN-gamma
• CPC Class Codes: A61K 38/30 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 insulin-like growth factor binding protein A61K38/1754
• CPC Class Codes: A61K 38/49 Urokinase; Tissue plasminogen activator
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides methods for identifying genes and pathways involved in plasticity. The invention applies some of these methods to identify genes that are differentially regulated in at least a portion of the nervous system of an individual subjected to conditions known to result in altered nervous system plasticity, i.e., dark rearing (DR) or monocular deprivation (MD). The genes are targets for pharmacological agents that modify plasticity. The invention also identifies biological pathways that are enriched in genes that are differentially regulated under conditions known to result in altered nervous system plasticity. The present invention further provides methods and compositions for modifying plasticity in the nervous system of a subject. The invention includes a method for modifying plasticity in the nervous system of a subject comprising administering a plasticity-modifying agent to the subject, wherein the plasticity-enhancing agent modulates a gene or pathway that is differentially regulated in developmental conditions that alter nervous system plasticity (e.g., DR or MD). The methods and compositions may be administered to a subject suffering from damage to the nervous system or from a neuropsychiatric disorder in order to enhance recovery, reorganization, or function of the nervous system. The methods optionally include administering a proteolysis-enhancing agent to the subject.

Claims

1. A method for modifying plasticity or aiding restoration of function in the nervous system of a subject comprising the step of:

administering a plasticity-modifying agent to a subject in need thereof, wherein the agent is administered either alone or in combination with one or more additional agents in an amount effective to modify nervous system plasticity, wherein the plasticity-modifying agent modulates a gene or pathway that is differentially regulated in at least a portion of the nervous system of an individual subjected to a plasticity-modifying condition.

2. The method of claim 1, wherein the condition is a neurodevelopmental disorder.

4. The method of claim 1, wherein the condition is a neuropsychiatric disorder.

6. The method of claim 1, wherein the condition is trauma to the nervous system caused by a condition such as stroke.

8. The method of claim 1, wherein the plasticity-modifying agent is IGF1 or a modulator of the IGF1 pathway.

9. The method of claim 1, wherein the plasticity-modifying agent is a modulator of the JAK/STAT pathway.

10. The method of claim 1, wherein the plasticity-modifying agent is IFNγ

.

11. The method of claim 1, wherein the plasticity-modifying agent is a statin.

12. The method of claim 1, which comprises administering a first agent that activates the IGF1 pathway and a second agent that activates the JAK/STAT pathway.

17. The method of claim 1, wherein the step of administering comprises steps of:

(1) administering a first plasticity-modifying agent to a subject following an event that damages the brain or spinal cord or following diagnosis of a neuropsychiatric or neurodevelopmental disorder for a first period of time;

(2) administering a second plasticity-modifying agent to the subject for a second period of time, wherein the second period of time is separate from the first period of time.

36. The method of claim 17, wherein the first plasticity-modifying agent is identical to the second plasticity-modifying agent.

37. The method of claim 17, wherein the first plasticity-modifying agent is not identical to the second plasticity-modifying agent.

57. The method of claim 1, further comprising administering a proteolysis-enhancing agent to the subject.

65. The method of claim 1, further comprising administering an agent selected from the group consisting of neural growth enhancing agents, which are optionally selected from among neurotransmitters or analogs thereof, neurally active growth factors, neural signaling molecules, neurally active small molecules, and neurally active metals.

3. (canceled)

5. (canceled)

7. (canceled)

13-16. -16. (canceled)

18-35. -35. (canceled)

38-56. -56. (canceled)

58-64. -64. (canceled)

66. (canceled)

67. A method for promoting recovery or reorganization in the nervous system of a subject comprising the step of:

administering a plasticity-modifying agent to a subject in need thereof, wherein the agent is administered either alone or in combination with one or more additional agents in an amount effective to promote recovery or reorganization in the nervous system, wherein the plasticity-modifying agent modulates a gene or pathway that is differentially regulated in at least a portion of the nervous system of an individual subjected to a plasticity-modifying condition.

68-77. -77. (canceled)

78. A method for promoting recovery or reorganization in the nervous system of a subject in need thereof comprising the step of:

administering to the subject a proteolysis-enhancing agent and an agent selected from the group consisting of;

agents that activate the IGF1 pathway, agents that activate the JAK/STAT pathway, agents that inhibit the development, survival, or activity of parvalbumin expressing interneurons, and agents that inhibit the expression of parvalbumin, wherein the proteolysis-enhancing agent is administered at least 3, 6, 12, 24, or more hours after a specific damaging event or diagnosis of a disorder and optionally also prior to 3 hours after the specific damaging event or diagnosis of a disorder.

79. A drug delivery device for implantation into the nervous system of a subject, the drug delivery device comprising:

a biocompatible polymer; and

a plasticity-modifying agent, wherein the plasticity-modifying agent is released from the polymer in an amount effective to modify plasticity in the nervous system of the subject.

80-82. -82. (canceled)

83. A composition comprising a plasticity-modifying agent and a proteolysis-enhancing agent.

84-85. -85. (canceled)

86. A method of identifying a gene involved in plasticity comprising steps of:

evaluating an individual in or subjecting an individual to a condition that modifies nervous system plasticity;

measuring level or activity of each of a plurality of genes in at least a portion of the individual'"'"'s nervous system; and

identifying one or more genes whose expression or activity is differentially regulated in the portion of the individual'"'"'s nervous system relative to its expression or activity under alternative conditions.

87-99. -99. (canceled)

100. A computer readable medium that stores information that identifies a set of genes whose expression or activity is differentially regulated in an individual subjected to a condition that modifies plasticity.

101. (canceled)