The invention relates to methods of reducing an immune response to a transgene product in a mammal by co-administration of a small-interfering ribonucleic acid (siRNA) molecule that temporarily inhibits or reduces transgene expression, wherein the siRNA is administered in an amount, and for a period of time, sufficient to reduce an immune response to the transgene product when it is expressed at therapeutic levels. The present invention further relates to methods of administering siRNAs to a mammal to reduce an immune response to an immunogenic protein, such as an enzyme used in enzyme replacement therapy.