Modulation of neural stem cells and neural progenitor cells

• US 20080213276A1
• Filed: 07/19/2007
• Published: 09/04/2008
• Est. Priority Date: 05/08/2002
• Status: Active Grant

• Current Assignee: Newron Sweden AB (Newron Pharmaceuticals Spa)
• Original Assignee: NeuroNova AB (Newron Pharmaceuticals Spa)
• Inventors: Lindquist, Per, Mercer, Alex, Wikstrom, Lilian, Ronnholm, Harriet
• Granted Patent: US 7,811,822 B2
• Time in Patent Office: Days
• US Class Current: 424/141.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 38/17 from animals; from humans enzyme inhibitors A61K38/005
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: G01N 33/5008 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/502 for testing non-proliferative effects
• CPC Class Codes: G01N 33/5058 Neurological cells
• CPC Class Codes: G01N 33/5073 Stem cells

Abstract

The invention relates generally to methods of influencing central nervous system cells to produce progeny useful in the treatment of CNS disorders. More specifically, the invention includes methods of exposing a patient suffering from such a disorder to a reagent that modulates the proliferation, migration, differentiation and survival of central nervous system cells via S1P or LPA signaling. These methods are useful for reducing at least one symptom of the disorder.

Claims

1. A method of alleviating a symptom of a disorder of the nervous system in a patient comprising administering an S1P, LPA or EDG receptor agonist or a combination thereof to modulate NSC activity in vivo to a patient suffering from the disorder of the nervous system.

2. The method of claim 1 wherein the EDG receptor is selected from the group consisting of EDG2, EDG3, EDG4 and EDG5.

3. The method of claim 1 wherein the EDG receptor is EDG1 or EDG8.

4. The method of claim 1 wherein the NSC activity is proliferation, migration or survival.

5. The method of claim 1 wherein the S1P, LPA or EDG receptor agonist or a combination thereof is administered in an amount of 0.1 ng/kg/day to 10 mg/kg/day.

6. The method of claim 1 wherein the S1P, LPA or EDG receptor agonist is administered to achieve a target tissue concentration of 0.1 nM to 10 μ

M.

7. The method of claim 6 wherein the target tissue is selected from the group consisting of the ventricular wall, the volume adjacent to the wall of the ventricular system, piriform cortex, hippocampus, alveus, striatum, substantia nigra, retina, nucleus basalis of Meynert, spinal cord, thalamus, hypothalamus piriform cortex and cortex.

8. The method of claim 1 wherein the S1P, LPA or EDG receptor agonist is administered by injection.

9. The method of claim 8 wherein the injection is given subcutaneously, intraperitoneally, intramusclularly, intracerebroventricularly, intraparenchymally, intrathecally or intracranially.

10. The method of claim 1 wherein the S1P, LPA or EDG receptor agonist is administered orally.

11. The method of claim 1 wherein the disorder of the nervous system is selected from the group consisting of neurodegenerative disorders, NSC disorders, neural progenitor disorders, ischemic disorders, neurological traumas, affective disorders, neuropsychiatric disorders, degenerative diseases of the retina, retinal injury/trauma, cognitive performance and learning and memory disorders.

12. A method of modulating the activity of an S1P, LPA, EDG receptor or a combination thereof, on a NSC comprising the step of exposing the cell expressing the receptor to a modulator agent, wherein the exposure induces an NSC to proliferate, differentiate, migrate or survive.

13. The method of claim 12 wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.

14. The method of claim 12 wherein the modulator agent is an exogenous reagent, an antibody, an affibody or a combination thereof.

15. The method of claim 12 wherein the modulator agent is selected from the group consisting of S1P, LPA or EDG receptor agonist.

16. The method of claim 12 wherein the modulator agent is pegylated.

17. The method of claim 14 wherein the antibody is a monoclonal or a polyclonal antibody.

18. The method of claim 12 wherein the NSC is derived from fetal brain, adult brain, neural cell culture or a neurosphere.

19. The method of claim 12 wherein the NSC is derived from tissue enclosed by dura mater, peripheral nerves or ganglia.

20. The method of claim 12 wherein the NSC is derived from stem cells originating from a tissue selected from the group consisting of pancreas, skin, muscle, adult bone marrow, liver, umbilical cord tissue and umbilical cord blood.

21. A method for stimulating mammalian adult NSC proliferation or neurogenesis comprising the step of contacting a cell population comprising mammalian adult NSC to a agent selected from the group consisting of an S1P, LPA or EDG receptor agonist to form a treated NSC, wherein the treated NSC cell shows improved proliferation or neurogenesis compared to untreated cells.

22. The method of claim 21 wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.

23. The method of claim 21 wherein the NSC is derived from lateral ventricle wall of a mammalian brain.

24. The method of claim 21 wherein the NSC is derived from stem cells originating from a tissue selected from the group consisting of pancreas, skin, muscle, adult bone marrow, liver, umbilical cord tissue and umbilical cord blood.

25. The method of claim 21 wherein the treated NSC shows improved survival, proliferation or migration compared to untreated cells.

26. A method for stimulating primary adult mammalian NSC to proliferate to form neurospheres comprising contacting the cell with an agent selected from the group consisting of an S1P, LPA or EDG receptor agonist to produce a proliferating NSC.

27. The method of claim 26 wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.

28. A method for inducing the in situ proliferation, migration or survival of an NSC located in the neural tissue of a mammal, the method comprising administering a therapeutically effective amount of an S1P, LPA or EDG receptor agonist to the neural tissue to induce the proliferation, migration or survival of the cell.

29. The method of claim 28 wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.

30. A method of enhancing neurogenesis in a patient suffering from a central nervous system disorder comprising the step of infusing an S1P, LPA or EDG receptor agonist thereof into the patient.

31. The method of claim 30 wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.

32. The method of claim 30 wherein the infusion is selected from the group consisting of intraventricular, intravenous, sublingual, subcutaneous and intraarterial infusion.

33. A method of alleviating a symptom of a central nervous system disorder in a patient comprising the step of infusing an S1P, LPA or EDG receptor agonist into the patient.

34-66. -66. (canceled)