AAV vectors are among the most promising to treat hereditary diseases by gene therapy. Long-term expression of therapeutic genes has been demonstrated in preclinical models and in clinical trials after AAV delivery in various tissues. In particular, AAV gene transfer to the retina resulted in long-term correction of RPE65 deficiency, a rare form of congenital blindness.1,2,3 Similarly, AAV-based gene therapy to the skeletal muscle resulted in a sustained reduction of postprandial chylomicron levels in patients afflicted by lipoprotein lipase (LPL) deficiency,4,5 possibly reducing the risk of pancreatitis, one of the hallmarks of this genetic disease. This latest clinical advance constitutes the basis of the first Marketing Authorization Approval—albeit under specific restrictive conditions—of a gene therapy product (i.e., Glybera, developed by uniQure) by the European Medicines Agency.6 AAV has also been explored since the 1990s as a vector to treat hemophilia B via clotting FIX gene therapy.7 Although FIX expression could be detected after liver-directed gene therapy, the levels were transient.8 This transience was possibly due to the immune clearance of transduced hepatocytes by AAV-specific T cells,9 consistent with the occurrence of transient liver toxicity as measured by elevated serum transaminases. In the muscle, however, FIX expression was sustained for 10 years and no transient toxicity was apparent, but the FIX production by the myofibers was insufficient to yield detectable FIX levels in the blood.10,11