Modulation of neural stem cells and neural progenitor 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.

We claim:  
     
         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 μM.  
     
     
         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, intramuselularly, 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 . A method for producing a cell population enriched for human NSC, comprising: 
 (a) contacting a cell population containing NSC with a reagent that recognizes a determinant on an S1P, LPA or EDG receptor; and    (b) selecting for cells in which there is contact between the reagent and the determinant on the surface of the cells of step (a) to produce a population highly enriched for central nervous system stem cells.    
     
     
         35 . The method of  claim 34  wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.  
     
     
         36 . The method of  claim 34  wherein the reagent is selected from the group consisting of a small molecule, a peptide, an antibody and an affibody.  
     
     
         37 . The method of  claim 34  wherein the population containing NSC are obtained from neural tissue.  
     
     
         38 . The method of  claim 34  wherein the cell population is derived from whole mammalian fetal brain or whole mammalian adult brain.  
     
     
         39 . The method of  claim 34  wherein the human NSCs are 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.  
     
     
         40 . An in vitro cell culture comprising a cell population generated by the method of  claim 34  wherein the cell population is enriched for cells expressing receptors selected from the group consisting of an S1P, LPA or EDG receptor.  
     
     
         41 . The in vitro cell culture of  claim 40  wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.  
     
     
         42 . A method for alleviating a symptom of a central nervous system disorder comprising administering the cell population of  claim 40  to a mammal in need thereof.  
     
     
         43 . A method of reducing a symptom of a central nervous system disorder in a patient comprising the step of administering into the spinal cord of the subject a composition comprising 
 (a) a population of isolated NSCs obtained from fetal or adult tissue; and    (b) an S1P, LPA or EDG receptor agonist or a combination thereof; whereby the symptom is reduced.    
     
     
         44 . The method of  claim 43  wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.  
     
     
         45 . A method of reducing a symptom of a central nervous disorder in a patient comprising the steps of: 
 (a) introducing a viral vector into the target cell, wherein the viral vector has at least one insertion site containing a nucleic acid which encodes an S1P, LPA or EDG receptor agonist, the nucleic acid gene operably linked to a promoter capable of expression in the host; and    (b) expressing the nucleic acid to produce a protein in a target cell to reduce the symptom.    
     
     
         46 . The method of  claim 45  wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.  
     
     
         47 . A method for alleviating a symptom of a disease or disorder of the nervous system in a patient comprising the steps of: 
 (a) providing a population of NSC;    (b) suspending the NSC in a solution comprising an S1P, LPA or EDG receptor agonist or a combination thereof to generate a cell suspension; and    (c) delivering the cell suspension to an injection site in the nervous system of the patient to alleviate the symptom.    
     
     
         48 . The method of  claim 47  wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.  
     
     
         49 . The method of  claim 47  further comprising the step of administering to the injection site a growth factor for a period of time before the step of delivering the cell suspension.  
     
     
         50 . The method of  claim 47  further comprising the step of administering to the injection site a growth factor after the delivering step.  
     
     
         51 . A method for transplanting a population of cells enriched for human NSC, comprising: 
 (a) contacting a population containing NSC with a reagent that recognizes a determinant on an S1P, LPA or EDG receptor;    (b) selecting for cells in which there is contact between the reagent and the determinant on the surface of the cells of step (a), to produce a population highly enriched for central nervous system stem cells; and    (c) implanting the selected cells of step (b) into a non-human mammal.    
     
     
         52 . The method of  claim 51  wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.  
     
     
         53 . A method of modulating an S1P, LPA or EDG receptor agonist on the surface of an NSC comprising the step of contacting the cell expressing the receptor to exogenous reagent, antibody, or affibody, wherein the exposure induces the NSC to proliferate, migrate or survive.  
     
     
         54 . The method of  claim 53  wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.  
     
     
         55 . The method of  claim 53  wherein the NSC is derived from fetal brain, adult brain, neural cell culture or a neurosphere.  
     
     
         56 . A method of determining an isolated candidate S1P, LPA or EDG receptor modulator compound for its ability to modulate NSC activity comprising the steps of: 
 (a) administering the isolated candidate compound to a non-human mammal; and    (b) determining if the candidate compound has an effect on modulating the NSC activity in the non-human mammal.    
     
     
         57 . The method of  claim 56  wherein the EDG receptor is selected from the group consisting of EDG1, EDG2, EDG3, EDG4, EDG5 and EDG8.  
     
     
         58 . The method of  claim 56  wherein the determining step comprises comparing the neurological effects of the non-human mammal with a referenced non-human mammal not administered the candidate compound.  
     
     
         59 . The method of  claim 56  wherein the NSC activity is proliferation, migration or survival.  
     
     
         60 . The method of  claim 56  wherein the S1P, LPA or EDG receptor modulator is administered by injection.  
     
     
         61 . The method of  claim 60  wherein the injection is given subcutaneously, intraperitoneally, intramuscluarly, intracerebroventricularly, intraparenchymally, intrathecally or intracranially.  
     
     
         62 . The method of  claim 56  wherein the S1P, LPA or EDG receptor modulator is administered via peptide fusion or micelle delivery.  
     
     
         63 . A method for synergistically stimulating mammalian adult NSC proliferation or neurogenesis comprising the step of contacting a cell population comprising mammalian adult neural stem cells to a growth factor and an agent selected from the group consisting of an S1P, LPA and EDG receptor agonist.  
     
     
         64 . The method of  claim 63  wherein the stimulation of mammalian adult NSC proliferation is greater than stimulation by the growth factor or stimulation by the agent alone.  
     
     
         65 . The method of  claim 63  wherein the stimulation of mammalian adult NSC proliferation is greater than the sum of stimulation by growth factor and stimulation by the agent.  
     
     
         66 . The method of  claim 63  wherein the growth factor is EGF.