Could potentially disrupt other genes. Difficult to manufacture in large quantities. The type that killed Jesse Gelsinger. One of the reasons for low expression is lack of a promoter with the gene. Gene doesn't get turned on.
Promoters are often too big for the virus carrier.
Using the virus's own promoter has worked poorly. Fuses with cell membrane, carries DNA inside, maybe to nucleus. Sickle-cell anemia caused by a single wrong nucleotide base. Changes the shape of the hemoglobin molecule. Most cystic fibrosis cases are caused by the deletion of 3 nucleotides.