An expression cassette for gene silencing and replacement, including, in operable communication, a promoter, an expression attenuator, a nucleotide sequence encoding a gene for a replacement target protein, and an shRNA sequence for knockdown of an endogenous variant of the target protein, wherein the promoter, the expression attenuator, the nucleotide sequence encoding the gene for the replacement target protein, and the shRNA are expressed as a single transcript. Also included are expression vectors and cells. Also included are methods of silencing and replacement of a target gene in a cell in culture by transforming the cells with the expression vectors described herein. Also included are minimal expression cassettes suitable for therapeutic methods.