Methods for treating neurological deficits

Abstract

The present invention features methods and compositions for treating a patient who has a neurological deficit. The method can be carried out, for example, by contacting (in vivo or in culture) a neural progenitor cell of the patient's central nervous system (CNS) with a polypeptide that binds the epidermal growth factor (EGF) receptor and directing progeny of the proliferating progenitor cells to migrate en masse to a region of the CNS in which they will reside and function in a manner sufficient to reduce the neurological deficit. The method may include a further step in which the progeny of the neural precursor cells are contacted with a compound that stimulates differentiation.

What is claimed is:  
     
         1 . A method for treating a patient who has a neurological deficit, the method comprising 
 (a) contacting a neural progenitor cell of the patient's central nervous system (CNS) with a polypeptide that binds the epidermal growth factor (EGF) receptor, the dosage of the polypeptide being sufficient to stimulate the proliferation of the neural progenitor cell, and    (b) directing progeny of the proliferating progenitor cell to migrate en masse to a region of the CNS in which the cells will reside and function in a manner sufficient to reduce the neurological deficit.    
     
     
         2 . The method of  claim 1 , further comprising contacting the cells with a compound that stimulates the progeny of the proliferating neural progenitor cells to differentiate.  
     
     
         3 . The method of  claim 1 , wherein the neurological deficit is caused by a neurodegenerative disease, a traumatic injury, a neurotoxic injury, ischemia, a developmental disorder, a disorder affecting vision, an injury or disease of the spinal cord, a demyelinating disease, an autoimmune disease, an infection, or an inflammatory disease.  
     
     
         4 . The method of  claim 3 , wherein the neurodegenerative disease is Alzheimer's Disease, Huntington's Disease, or Parkinson's Disease.  
     
     
         5 . The method of  claim 3 , wherein the ischemia is associated with a stroke.  
     
     
         6 . The method of  claim 1 , wherein the polypeptide that binds the EGF receptor is amphiregulin (AR), betacellulin (BTC), epidermal growth factor (EGF), epiregulin (ER), heparin-binding EGF-like growth factor (HB-EGF), schwannoma-derived growth factor (SDGF), myxomavirus growth factor Shope fibroma virus growth factor, teratocarcinoma-derived growth factor-1 (TDGF-1), transforming growth factor alpha (TGFα), or vaccinia growth factor (VGF).  
     
     
         7 . The method of  claim 1 , wherein the polypeptide that binds the EGF receptor is TGFα.  
     
     
         8 . The method of  claim 1 , wherein the neural progenitor cell is contacted in vivo with a polypeptide that binds the EGF receptor.  
     
     
         9 . The method of  claim 1 , wherein the neural progenitor cell is contacted in culture with a polypeptide that binds the EGF receptor.  
     
     
         10 . The method of  claim 1 , wherein migration is directed by contacting a cell along, or at the end of, a desired path of migration with a compound that increases the expression of a cell adhesion molecule or extracellular matrix molecule.  
     
     
         11 . The method of  claim 10 , wherein the compound is TGFα.  
     
     
         12 . The method of  claim 10 , wherein the cell adhesion molecule is fibronectin.  
     
     
         13 . The method of  claim 10 , wherein the cell adhesion molecule is laminin.  
     
     
         14 . The method of  claim 10 , wherein the compound is applied along the path between the neural precursor cells and the location to which their progeny are directed to migrate.  
     
     
         15 . The method of  claim 1 , wherein migration is directed by contacting the cells along a desired migratory path with a compound that inhibits a naturally occurring signal along the path, the naturally occurring signal being a signal that inhibits migration.  
     
     
         16 . The method of  claim 1 , wherein migration is directed by mechanically disrupting tissue in the CNS.  
     
     
         17 . The method of  claim 1 , wherein migration is directed by neurochemically blocking the activity of cells in the CNS.  
     
     
         18 . The method of  claim 2 , wherein the compound that stimulates differentiation is retinoic acid or brain-derived neurotrophic factor.  
     
     
         19 . A method for treating a patient who has a neurological deficit, the method comprising 
 (a) contacting a neural progenitor cell of the patient's central nervous system (CNS) with a polypeptide that binds the epidermal growth factor (EGF) receptor, the dosage of the polypeptide being sufficient to stimulate the proliferation of the neural progenitor cell;    (b) directing the progeny of the proliferating progenitor cells to migrate en masse to a second region of the CNS; and    (c) contacting the cells that have migrated with a compound that stimulates differentiation.    
     
     
         20 . The method of  claim 19 , wherein the compound that stimulates the proliferation of neural stem cells and the compound that stimulates differentiation are administered sequentially.  
     
     
         21 . A pharmaceutical composition comprising a polypeptide that binds the epidermal growth factor (EGF) receptor and a compound that stimulates the differentiation of neural progenitor cells.  
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the polypeptide that binds the EGF receptor is TGFα.  
     
     
         23 . The pharmaceutical composition of  claim 21 , wherein the polypeptide that binds the EGF receptor is TGFα and the compound that stimulates the differentiation of neural progenitor cells is brain-derived neurotrophic factor.  
     
     
         24 . The method of  claim 1 , wherein the injury to the central nervous system is an injury to the spinal cord.  
     
     
         25 . The method of  claim 1 , wherein the injury to the central nervous system is an injury to the retina.  
     
     
         26 . A method for treating a subject having a neurological deficit, the method comprising contacting a neural precursor cell in vivo with a therapeutically effective amount of a polypeptide that binds the epidermal growth factor (EGF) receptor, wherein the polypeptide is parentally administered to the subject, and wherein the administration induces the proliferation, migration, or differentiation of a neural precursor cell in a manner sufficient to treat the neurological deficit.  
     
     
         27 . The method of  claim 26 , wherein the neurological deficit is caused by a neurodegenerative disease, a traumatic injury, a neurotoxic injury, ischemia, a developmental disorder, a disorder affecting vision, an injury or disease of the spinal cord, a demyelinating disease, an autoimmune disease, an infection, or an inflammatory disease.  
     
     
         28 . The method of  claim 27 , wherein the neurodegenerative disease is Alzheimer's Disease, Huntington's Disease, or Parkinson's Disease.  
     
     
         29 . The method of  claim 27 , wherein the ischemia is associated with a stroke.  
     
     
         30 . The method of  claim 26 , wherein the polypeptide that binds the EGF receptor is amphiregulin (AR), betacellulin (BTC), epidermal growth factor (EGF), epiregulin (ER), heparin-binding EGF-like growth factor (HB-EGF), schwannoma-derived growth factor (SDGF), myxomavirus growth factor Shope fibroma virus growth factor, teratocarcinoma-derived growth factor-1 (TDGF-1), transforming growth factor alpha (TGFα), or vaccinia growth factor (VGF).  
     
     
         31 . The method of  claim 26 , wherein the polypeptide that binds the EGF receptor is TGFα.  
     
     
         32 . The method of  claim 26 , wherein migration is directed by contacting a cell along, or at the end of, a desired path of migration with a compound that increases the expression of a cell adhesion molecule or extracellular matrix molecule.  
     
     
         33 . The method of  claim 32 , wherein the compound is TGFβ.  
     
     
         34 . The method of  claim 32 , wherein the cell adhesion molecule is fibronectin.  
     
     
         35 . The method of  claim 32 , wherein the cell adhesion molecule is laminin.  
     
     
         36 . The method of  claim 32 , wherein the compound is applied along the path between the neural precursor cells and the location to which their progeny are directed to migrate.  
     
     
         37 . The method of  claim 26 , wherein migration is directed by contacting the cells along a desired migratory path with a compound that inhibits a naturally occurring signal along the path, the naturally occurring signal being a signal that inhibits migration.  
     
     
         38 . The method of  claim 26 , wherein migration is directed by mechanically disrupting tissue in the CNS.  
     
     
         39 . The method of  claim 26 , wherein migration is directed by neurochemically blocking the activity of cells in the CNS.  
     
     
         40 . The method of  claim 26 , wherein differentiation is stimulated by retinoic acid or brain-derived neurotrophic factor.  
     
     
         41 . A method for treating a subject having a neurological deficit, the method comprising 
 (a) contacting a neural precursor cell in vivo with a therapeutically effective amount of a polypeptide that binds the epidermal growth factor (EGF) receptor, wherein the polypeptide is parenterally administered in a dosage sufficient to stimulate the proliferation of the neural progenitor cell;    (b) directing the progeny of the proliferating progenitor cells to migrate en masse to a second region of the CNS; and    (c) contacting the cells that have migrated with a compound that stimulates differentiation.    
     
     
         42 . The method of  claim 41 , wherein the polypeptide that stimulates the proliferation of neural stem cells and the compound that stimulates differentiation are administered sequentially.  
     
     
         43 . A pharmaceutical composition comprising a polypeptide that binds the epidermal growth factor (EGF) receptor and a compound that stimulates the differentiation of neural precursor cells.  
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein the polypeptide that binds the EGF receptor is TGFα.  
     
     
         45 . The pharmaceutical composition of  claim 43 , wherein the polypeptide that binds the EGF receptor is TGFα and the compound that stimulates the differentiation of neural precursor cells is brain-derived neurotrophic factor.  
     
     
         46 . The method of  claim 26 , wherein the injury to the central nervous system is an injury to the spinal cord.  
     
     
         47 . The method of  claim 26 , wherein the injury to the central nervous system is an injury to the retina.