Potency is a key optimization parameter for hemophilia A gene therapy product candidates. Optimization strategies include promoter engineering to increase transcription， codon optimization of mRNA to improve translation， and amino-acid substitution to promote secretion. Herein， we describe both rational and empirical design approaches to the development of a minimally sized， highly potent AAV-fVIII vector that incorporates three unique elements: a liver-directed 146-nt transcription regulatory module， a target-cell-specific codon optimization algorithm， and a high-expression bioengineered fVIII variant. The minimal synthetic promoter allows for the smallest AAV-fVIII vector genome known at 4，832 nt， while the tissue-directed codon optimization strategy facilitates increased fVIII transgene product expression in target cell types， e.g.， hepatocytes， over traditional genome-level codon optimization strategies. As a tertiary approach， we incorporated ancient and orthologous fVIII sequence elements previously shown to facilitate improved biosynthesis through post-translational mechanisms. Together， these technologies contribute to an AAV-fVIII vector that confers sustained， curative levels of fVIII at a minimal dose in hemophilia A mice. Moreover， the first two technologies should be generalizable to all liver-directed gene therapy vector designs.