Compounds and methods to enhance rAAV transduction

A method to enhance the expression of a transgene operably linked to an expression control sequence in a mammalian lung cell or a mammalian liver cell, comprising:

• contacting the mammalian lung cell or the mammalian liver cell with an amount of a proteasome inhibitor and directly administering a recombinant AAV (rAAV) comprising the transgene, wherein the amount enhances expression of the transgene, wherein the expression is enhanced relative to expression in a mammalian lung cell or a mammalian liver cell comprising the rAAV but that is not contacted with the proteasome inhibitor, wherein the inhibitor has two amino acids linked by a peptide bond or three amino acids linked by peptide bonds, which inhibitor optionally has a N-terminal blocking group, a C-terminal blocking group, or both.

A method comprising:

• providing a mammal having cells subjected to therapy with a rAAV comprising a transgene operably linked to an expression control sequence, the expression of which in the mammal is therapeutic, and administering to the mammal a proteasome inhibitor in an amount effective to enhance expression of the transgene in the cells of the mammal wherein the expression is enhanced relative to expression in cells in a mammal comprising the rAAV but that are not contacted with the proteasome inhibitor, wherein the inhibitor has two amino acids linked by a peptide bond or three amino acids linked by peptide bonds, which inhibitor optionally has a N-terminal blocking group, a C-terminal blocking group, or both.

A method to enhance AAV transduction of a mammalian cell, comprising:

• directly contacting the mammalian cell with the AAV and administering a proteasome inhibitor in an amount effective to enhance transduction of the AAV wherein the transduction is enhanced relative to a mammal having cells contacted with the AAV but that is not administered the proteasome inhibitor, wherein the inhibitor has two amino acids linked by a peptide bond or three amino acids linked by peptide bonds, which inhibitor optionally has a N-terminal blocking group, a C-terminal blocking group, or both.

A method to enhance AAV transduction in a mammal in need of therapy,

• comprising:
• directly administering to the mammal a rAAV encoding a therapeutic gene product encoded by an open reading frame operably linked to an expression control sequence and administering a proteasome inhibitor in an amount effective to enhance transduction of the rAAV wherein the transduction is enhanced relative to transduction in cells of a mammal comprising the rAAV but that is not administered the inhibitor, wherein the inhibitor has two amino acids linked by a peptide bond or three amino acids linked by peptide bonds, which inhibitor optionally has a N-terminal blocking group, a C-terminal blocking group, or both.

The method of 1, 4, 8, 13, or 14 wherein one of the amino acids is a non-naturally occurring amino acid.

The method of 1, 4, 8, 13, or 14 wherein the proteasome inhibitor is directly administered.