Compounds and methods to enhance rAAV transduction

Abstract

Agents and methods to alter rAAV transduction are provided.

1 - 32 . (canceled) 
     
     
         33 . A method to inhibit or treat a condition associated with aberrant expression of an endogenous gene product, comprising: contacting a mammal at risk of or having the condition, with an effective amount of at least one agent that enhances AAV transduction and an effective amount at least one rAAV comprising a transgene encoding at least a portion of a functional gene product, the expression of which in the mammal inhibits or treats at least one symptom of the condition, wherein the agent is a chemotherapeutic, a lipid lowering agent, an antibiotic or a food additive. 
     
     
         34 . The method of  claim 33  wherein the aberrant expression is the lack of or reduced expression of the endogenous gene product. 
     
     
         35 . The method of  claim 33  wherein one rAAV comprises a first recombinant DNA molecule comprising linked:
 i) a first DNA segment comprising a 5′ ITR of AAV;   ii) a second DNA segment comprising a heterologous DNA; and   iii) a third DNA segment comprising a 3′ ITR of AAV.   
     
     
         36 . The method of  claim 35  further comprising a second rAAV comprises a second recombinant DNA molecule comprising linked:
 i) a first DNA segment comprising a 5′ ITR of AAV, and   ii) a second DNA segment comprising a heterologous DNA which has sequences which are different than the sequences in the second DNA segment of the first recombinant DNA molecule; and   iii) a third DNA segment comprising a 3′ ITR of AAV.   
     
     
         37 . The method of  claim 36  wherein the second DNA segment of the first recombinant DNA molecule comprises a portion of an open reading frame for a gene product, optionally linked to a transcriptional regulatory element, and a splice donor site 3′ to the portion of the open reading frame, wherein the second DNA segment of the second recombinant DNA molecule comprises a splice acceptor site 5′ to the remainder of an open reading frame, which together with the second DNA segment of the first recombinant DNA molecule encodes a functional gene product. 
     
     
         38 . The method of  claim 37  wherein the transcriptional regulatory element is a promoter. 
     
     
         39 . The method of  claim 36  wherein the second DNA segment of the first recombinant DNA molecule comprises an enhancer and the second DNA segment of the second recombinant DNA molecule comprises an open reading frame encoding a functional gene product. 
     
     
         40 . The method of  claim 36  wherein the second DNA segment of the first recombinant DNA molecule comprises a promoter and the second DNA segment of the second recombinant DNA molecule comprises an open reading frame encoding a functional gene product. 
     
     
         41 . The method of  claim 33  wherein the expression of the transgene is enhanced. 
     
     
         42 . The method of  claim 33  wherein the transgene encodes cystic fibrosis transmembrane conductance regulator, β-globin, γ-globin, tyrosine hydroxylase, glucocerebrosidase, aryl sulfatase A, factor VIII, dystrophin or erythropoietin. 
     
     
         43 - 50 . (canceled) 
     
     
         51 . The method of  claim 33  wherein at least one agent modulates microfilaments or microtubules. 
     
     
         52 . The method of  claim 33  wherein at least one agent modulates rAAV endocytosis. 
     
     
         53 . The method of  claim 33  wherein at least one agent modulates rAAV trafficking in the cell. 
     
     
         54 . The method of  claim 33  wherein at least one agent modulates rAAV processing in the cell. 
     
     
         55 . The method of  claim 33  wherein at least one agent modulates rAAV nucleic acid degradation in the cell. 
     
     
         56 . The method of  claim 33  wherein at least one agent modulates rAAV protein degradation in the cell. 
     
     
         57 . The method of  claim 33  wherein at least one agent modulates rAAV transport to the nucleus. 
     
     
         58 . The method of  claim 33  wherein at least one agent modulates viral genome transport to the nucleus. 
     
     
         59 . The method of  claim 33  wherein at least one agent modulates subcellular localization of proteosomes. 
     
     
         60 . The method of  claim 33  wherein at least one agent is epoxomicin, doxorubicin, doxil, daunorubicin, idarubicin, epirubicin, aclarubicin, simvastatin or tannic acid.