Immunoadsorption

Abstract

Upon administration of rAAV vectors the humoral immune response (neutralizing antibodies) is the first barrier that needs to be overcome. Surprisingly it was found that by using immunoadsorption for depletion of immunoglobulins from the blood (plasma), subjects can be highly efficiently treated with rAAV vectors, i.e. obtain highly efficient transduction after rAAV vector administration, in spite of the presence of high levels of nAb.

1 - 20 . (canceled) 
     
     
         21 . A method of administering a recombinant adeno-associated virus (rAAV) to a subject, the method comprising
 (a) depleting a subject's immunoglobulins from
 (i) cerebrospinal fluid (CSF) by contacting the subject's CSF with an extracorporeal device for immunoadsorption, the device comprising a binding moiety attached to a matrix, wherein the binding moiety binds immunoglobulins; or 
 (ii) CSF and blood by contacting the subject's CSF with an extracorporeal device for immunoadsorption, the device comprising a binding moiety attached to a matrix, wherein the binding moiety binds immunoglobulins; and by contacting the subject's blood with an extracorporeal device for immunoadsorption, the device comprising a binding moiety attached to a matrix, wherein the binding moiety binds immunoglobulins; and 
   (b) subsequently administering an rAAV to the subject.   
     
     
         22 . The method according to  claim 21 , wherein the rAAV is administered intravenously. 
     
     
         23 . The method according to  claim 21 , wherein the rAAV is administered to the central nervous system. 
     
     
         24 . The method according to  claim 21 , wherein depleting the immunoglobulins comprises:
 (a) utilizing a binding moiety that binds immunoglobulins, and/or   (b) utilizing a binding moiety that binds anti-rAAV immunoglobulins.   
     
     
         25 . The method according to  claim 21 , wherein the immunoglobulins in the subject's CSF or CSF and blood are depleted by at least 90%. 
     
     
         26 . The method according to  claim 21 , wherein (a) is performed at least two times before (b) is performed. 
     
     
         27 . The method according to  claim 26 , wherein (a) is performed at least 5 times. 
     
     
         28 . The method according to  claim 21 , further comprising subjecting the subject to plasma exchange before (b) is performed. 
     
     
         29 . The method according to  claim 21 , further comprising administering an immune suppressing pharmaceutical. 
     
     
         30 . A method of decreasing a humoral immune response to a recombinant adeno-associated virus (rAAV) gene therapy in a subject, the method comprising:
 (a) contacting the subject's:
 (i) cerebrospinal fluid (CSF) with an extracorporeal device comprising a binding moiety that selectively binds anti-AAV immunoglobulins, wherein the binding moiety is attached to a matrix, thereby decreasing the humoral immune response to the rAAV gene therapy, or 
 (ii) CSF with an extracorporeal device comprising a binding moiety that selectively binds anti-AAV immunoglobulins, wherein the binding moiety is attached to a matrix, and blood with an extracorporeal device comprising a binding moiety that selectively binds anti-AAV immunoglobulins, wherein the binding moiety is attached to a matrix, thereby decreasing the humoral immune response to the rAAV gene therapy; 
   (b) subsequently administering rAAV therapy to the subject.   
     
     
         31 . A method for reducing an anti-rAAV immunoglobulin concentration in the cerebrospinal fluid (CSF) of a subject, the method comprising:
 (a) obtaining CSF from the subject, wherein the CSF comprises neutralizing antibodies that bind to a rAAV as a result of previously receiving a treatment comprising an rAAV vector,   (b) contacting the CSF with an extracorporeal immunoadsorption device, the device comprising a binding moiety attached to a matrix, wherein the binding moiety comprises an AAV epitope that is known to generate anti-AAV antibodies to selectively bind anti-rAAV immunoglobulins,   (c) administering the CSF subjected to immunoadsorption to the subject, thereby reducing the anti-rAAV immunoglobulin concentration in the subject's CSF.   
     
     
         32 . The method according to 31, further comprising:
 (a) obtaining blood from the subject, wherein the blood comprises neutralizing antibodies that bind to the rAAV as a result of previously receiving a treatment comprising an rAAV vector,   (b) separating the blood into plasma components and cellular components,   (c) contacting the plasma components with the extracorporeal device,   (d) reconstituting the blood by combining the cellular components with the plasma components that were subjected to immunoadsorption, and   (e) administering the reconstituted blood to the subject, thereby reducing the anti-rAAV immunoglobulin concentration in the subject's blood.   
     
     
         33 . The method according to  claim 31 , further comprising administering an rAAV vector to the subject. 
     
     
         34 . The method according to  claim 33 , wherein the rAAV vector is administered to the subject's central nervous system. 
     
     
         35 . The method according to  claim 32 , wherein the rAAV is administered intravenously. 
     
     
         36 . The method according to  claim 31 , wherein the anti-rAAV immunoglobulin concentration in the CSF is depleted by at least 90%. 
     
     
         37 . The method according to  claim 32 , wherein the anti-rAAV immunoglobulin concentration in the CSF and the blood is depleted by at least 90%. 
     
     
         38 . The method according to  claim 32 , further comprising subjecting the subject to plasma exchange. 
     
     
         39 . The method according to  claim 31 , further comprising administering an immune suppressing pharmaceutical. 
     
     
         40 . The method according to  claim 31 , wherein the binding moiety is selected from the group consisting of AAV capsids, AAV VP1, AAV VP2, AAV VP3, and AAV capsid peptides.