Diagram of the generation and transduction of a self-complementary AAV vector as compared to that of a conventional recombinant AAV. Left panel: According to the AAV DNA replication scheme, full-length rAAV genomes of both polarities are generated from duplex monomeric (DM) and duplex dimeric (DD) replicative intermediates and individually packaged in AAV capsids. In the nucleus of transduced cells the single-stranded genomes can either be a target for degradation or be converted into transcriptionally active double-stranded templates. The single-to-double strand DNA conversion depends on complementary chain synthesis or on the recruitment of a complementary genome (i.e., intermolecular hybridization). Right panel: According to the same replication model, a rAAV genome with roughly half the size of the wild-type AAV DNA and with one trs mutated, generates DD replicative intermediates with an inverted repeat configuration containing wild-type ITRs at the extremities and mutated ITRs at the axis of symmetry. Single-stranded molecules derived from these DNA structures are packaged in AAV capsids. After uncoating in the target cell nucleus, these molecules can readily fold into double-stranded templates through intramolecular base pairing due to their self-complementary nature (i.e., intramolecular hybridization).