Methods and compositions for attenuating gene expression modulating anti-viral transfer vector immune responses

Abstract

Provided herein are methods and related compositions for administering viral transfer vectors and antigen-presenting cell targeted immunosuppressants.

1 . A method comprising:
 establishing an anti-gene expression modulating viral transfer vector attenuated response in a subject by concomitant administration of an antigen-presenting cell targeted immunosuppressant and gene expression modulating viral transfer vector to the subject,   wherein the subject does not have pre-existing immunity against the gene expression modulating viral transfer vector.   
     
     
         2 - 3 . (canceled) 
     
     
         4 . A method comprising:
 establishing an anti-gene expression modulating viral transfer vector attenuated response in a subject by concomitant administration of an antigen-presenting cell targeted immunosuppressant and gene expression modulating viral transfer vector to the subject, and   administering to the subject one or more repeat doses of the gene expression modulating viral transfer vector.   
     
     
         5 - 7 . (canceled) 
     
     
         8 . The method of  claim 1 , further comprising administering to the subject one or more repeat doses of the viral transfer vector subsequent to the concomitant administration of the viral transfer vector and the antigen-presenting cell targeted immunosuppressant to the subject. 
     
     
         9 . A method comprising:
 determining a level of pre-existing immunity to a gene expression modulating viral transfer vector in a subject prior to administration of the gene expression modulating viral transfer vector to the subject,   concomitantly administering to the subject an antigen-presenting cell targeted immunosuppressant and gene expression modulating viral transfer vector, and   administering to the subject a dose of the gene expression modulating viral transfer vector.   
     
     
         10 . The method of  claim 9 , wherein the determining comprises measuring a level of anti-viral transfer vector antibodies in the subject prior to administration of the viral transfer vector to the subject. 
     
     
         11 - 14 . (canceled) 
     
     
         15 . A method comprising:
 escalating transgene expression of a gene expression modulating viral transfer vector in a subject by repeatedly, concomitantly administering to the subject an antigen-presenting cell targeted immunosuppressant and gene expression modulating viral transfer vector.   
     
     
         16 - 30 . (canceled) 
     
     
         31 . A method comprising:
 determining the frequency and dosing of concomitant administration of an antigen-presenting cell targeted immunosuppressant and gene expression modulating viral transfer vector in order to generate an anti-gene expression modulating viral transfer vector attenuated response in a subject, and   directing the concomitant administration of the antigen-presenting cell targeted immunosuppressant and gene expression modulating viral transfer vector to a subject according to the determined frequency and dosing.   
     
     
         32 - 37 . (canceled) 
     
     
         38 . The method of  claim 31 , wherein the subject does not have pre-existing immunity against the viral transfer vector. 
     
     
         39 . The method of  claim 31 , wherein the concomitant administration is simultaneous administration. 
     
     
         40 . The method of  claim 1 , wherein the subject is one to which the viral transfer vector has not been previously administered. 
     
     
         41 . The method of  claim 1 , wherein the viral transfer vector is a retroviral transfer vector, an adenoviral transfer vector, a lentiviral transfer vector or an adeno-associated viral transfer vector. 
     
     
         42 - 46 . (canceled) 
     
     
         47 . The method of  claim 1 , wherein the gene expression modulating transgene encodes a DNA-binding protein or a therapeutic RNA. 
     
     
         48 - 54 . (canceled) 
     
     
         55 . The method of  claim 1 , wherein the antigen-presenting cell targeted immunosuppressant comprises a negatively-charged particle. 
     
     
         56 - 64 . (canceled) 
     
     
         65 . The method of  claim 1 , wherein the antigen-presenting cell targeted immunosuppressant comprises synthetic nanocarriers comprising an immunosuppressant. 
     
     
         66 . The method of  claim 65 , wherein the synthetic nanocarriers further comprise a viral transfer vector antigen. 
     
     
         67 . (canceled) 
     
     
         68 . The method of  claim 65 , wherein the immunosuppressant and/or the antigen, if present, are/is encapsulated in the synthetic nanocarriers. 
     
     
         69 . The method of  claim 65 , wherein the synthetic nanocarriers comprise lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles or peptide or protein particles. 
     
     
         70 - 75 . (canceled) 
     
     
         76 . The method of  claim 65 , wherein the mean of a particle size distribution obtained using dynamic light scattering of a population of the synthetic nanocarriers is a diameter greater than 110 nm. 
     
     
         77 - 89 . (canceled) 
     
     
         90 . The method of  claim 65 , wherein the load of immunosuppressant comprised in the synthetic nanocarriers, on average across the synthetic nanocarriers, is between 0.1% and 50% (weight/weight). 
     
     
         91 - 94 . (canceled) 
     
     
         95 . The method of  claim 65 , wherein the immunosuppressant is rapamycin. 
     
     
         96 . (canceled)