This technology includes a new set of synthetic PCCB genes that can be used to treat propionic acidemia (PA) caused by propionyl-coA carboxylase beta (PCCB) mutations. The amino acid sequence of PCCB was reverse translated, using a variety of algorithms and expert input, to generate novel DNA sequences encoding PCCB (synPCCB1-5) expected to have increased expression. Next, the synPCCB sequences were cloned into a canonical adeno-associated virus (AAV) vector and tested for expression in human cells to demonstrate that the codon optimized alleles showed improved expression compared to the wild type (WT) PCCB gene. Finally, a synPCCBl AAV was pseudoserotyped with a serotype 9 capsid and used to rescue Pech-I- knock-out mice from neonatal lethality and improve their clinical and metabolic phenotypes.