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The Food and Drug Administration has approved seven AAV \u201cdrugs\u201d for one-time treatment respectively for Leber\u2019s congenital amaurosis, spinal muscular atrophy, hemophilia B, Duchenne muscular dystrophy, hemophilia A, and aromatic L-amino acid decarboxylase deficiency. Despite these remarkable developments, it has become increasingly clear that the first generation of AAV vectors is less than optimal since in most, if not all, cases, exceedingly high doses are needed to achieve clinical efficacy, and as a consequence, in some patients, serious adverse events have been observed, and to date, at least 21 patients have died. 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