Immunomodulating gene therapy

A method of enhancing the efficacy of protein replacement therapy in a human subject in need thereof that has pre-existing antibodies for a therapeutic protein administered for the protein replacement therapy, the method comprising:

• (i) administering to the subject a therapeutic amount of the therapeutic protein for the protein replacement therapy,
• wherein
• (a) the therapeutic protein is glucocerebrosidase, a-galactosidase A, sphingomyelinase, glycosaminoglycan, or α-glucosidase (GAA);
• and
• (ii) administering to the subject a dose of an adeno-associated viral (AAV) vector comprising a nucleic acid sequence encoding the therapeutic protein, operably linked to a liver-specific promoter,
• wherein following the administering of the AAV vector, an adverse immune response to the therapeutic protein administered in step (i) by the subject is reduced, and
• wherein the therapeutic efficacy of the therapeutic protein administered in step (i) is thereby enhanced.