Method for mobilizing stem and/or progenitor cells

Abstract

The present disclosure relates to methods for mobilizing stem and/or progenitor cells which are VLA-4 positive to the peripheral blood of a subject or from a tissue. The method comprises administering to the subject or tissue an effective amount of an antisense compound to VLA-4.

1 - 24 . (canceled) 
     
     
         25 . A method for mobilizing CD34 positive, α4 integrin positive, multipotent and/or oligopotent cells to the peripheral blood of a human subject, the method comprising administering to the human subject an effective amount of an antisense compound to α4 integrin. 
     
     
         26 . The method of  claim 25 , wherein the cells are mobilized from the bone marrow. 
     
     
         27 . The method of  claim 25 , wherein the cells are hematopoietic stem and/or progenitor cells. 
     
     
         28 . The method of  claim 25 , wherein the antisense compound is: 
       
         
           
                 
                 
               
                     
                   5′-  Me C Me UG AGT  Me CTG TTT  Me U Me C Me C A Me U Me U 
                 
                     
                     
                 
                     
                     Me C Me U -3′ 
                 
             
                
                
                
               
            
           
         
         wherein, 
         a) each of the 19 internucleotide linkages of the oligonucleotide is an O,O-linked phosphorothioate diester; 
         b) the nucleotides at the positions 1 to 3 from the 5′ end are 2′-O-(2-methoxyethyl) modified ribonucleosides; 
         c) the nucleotides at the positions 4 to 12 from the 5′ end are 2′-deoxyribonucleosides; 
         d) the nucleotides at the positions 13 to 20 from the 5′ end are 2′-O-(2-methoxyethyl) modified ribonucleosides; and 
         e) all cytosines are 5-methylcytosines ( Me C), 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         29 . The method of  claim 25 , wherein the cells are mesenchymal or endothelial progenitor cells. 
     
     
         30 . The method of  claim 25 , further comprising administering:
 (i) a growth factor or analogue thereof, or a CXCR4 inhibitor prior to, subsequently, or concurrently with the antisense compound; and/or   (ii) low dose chemotherapy or an additional α4 integrin antagonist prior to, subsequently, or concurrently with the antisense compound.   
     
     
         31 . The method of  claim 30 , wherein the growth factor is G-CSF, GM-CSF, SDF-1, or SCF. 
     
     
         32 . The method of  claim 25 , further comprising harvesting the mobilized cells. 
     
     
         33 . The method of  claim 32 , wherein the cells are harvested at least 4 days after administration of the antisense compound. 
     
     
         34 . The method of  claim 32 , further comprising monitoring:
 (i) the number of CD34 positive multipotent and/or oligopotent cells in the peripheral blood prior to harvesting the cells; and/or   (ii) the number of B cells, CD4 +  T cells, CD8 +  T cells, natural killer cells, monocytes, dendritic cells, platelets, neutrophils, eosinophils and/or basophils in the peripheral blood prior to harvesting the mobilized cells; and/or   (iii) the C max  and/or C trough  plasma levels of the antisense compound prior to harvesting the cells.   
     
     
         35 . The method of  claim 34 , wherein the cells are monitored:
 (i) by colony forming units or flow cytometry; and/or   (ii) for expression of one or more cell surface antigenic determinants.   
     
     
         36 . The method of  claim 34 , wherein the cells are harvested:
 (i) following a reduction in the number of one or more of B cells, CD4 +  T cells, neutrophils, eosinophils and/or basophils, and/or   (ii) when the C trough  is between 20 to 45 ng/mL.   
     
     
         37 . A method for mobilizing CD34 positive, multipotent and/or oligopotent cells to the peripheral blood of a human subject, the method comprising administering to the human subject an effective amount of antisense compound: 
       
         
           
                 
                 
               
                     
                   5′-  Me C Me UG AGT  Me CTG TTT  Me U Me C Me C A Me U Me U 
                 
                     
                     
                 
                     
                     Me C Me U -3′ 
                 
             
                
                
                
               
            
           
         
         wherein, 
         a) each of the 19 internucleotide linkages of the oligonucleotide is an O,O-linked phosphorothioate diester; 
         b) the nucleotides at the positions 1 to 3 from the 5′ end are 2′-O-(2-methoxyethyl) modified ribonucleosides; 
         c) the nucleotides at the positions 4 to 12 from the 5′ end are 2′-deoxyribonucleosides; 
         d) the nucleotides at the positions 13 to 20 from the 5′ end are 2′-O-(2-methoxyethyl) modified ribonucleosides; and 
         e) all cytosines are 5-methylcytosines ( Me C), 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . The method of  claim 37 , wherein the cells are mobilized from the bone marrow. 
     
     
         39 . The method of  claim 37 , wherein the cells are hematopoietic stem and/or progenitor cells. 
     
     
         40 . The method of  claim 37 , wherein the cells are mesenchymal or endothelial progenitor cells. 
     
     
         41 . The method of  claim 37 , further comprising administering:
 (i) a growth factor or analogue thereof, or a CXCR4 inhibitor prior to, subsequently, or concurrently with the antisense compound; and/or   (ii) low dose chemotherapy or an α4 integrin antagonist prior to, subsequently, or concurrently with the antisense compound.   
     
     
         42 . The method of  claim 37 , further comprising harvesting the mobilized cells. 
     
     
         43 . A method for the treatment of failure or dysfunction of normal blood cell production and maturation, hematopoietic malignancy, autoimmune disease, liver disease, or immunodeficiency, the method comprising administering cells harvested following a method for mobilizing according to  claim 25  to a subject in need. 
     
     
         44 . The method according to  claim 43 , wherein the cells are allogeneic cells or autologous cells. 
     
     
         45 . A method for the treatment of failure or dysfunction of normal blood cell production and maturation, hematopoietic malignancy, autoimmune disease, liver disease, or immunodeficiency, the method comprising administering cells harvested following a method for mobilizing according to  claim 37  to a subject in need. 
     
     
         46 . The method according to  claim 45 , wherein the cells are allogeneic cells or autologous cells.