Extrachromosomal Recombinant Adeno-Associated Virus Vector Genomes Are Primarily Responsible for Stable Liver Transduction In Vivo

Long-term correction of hyperphenylalaninemia by AAV-mediated gene transfer leads to behavioral recovery in phenylketonuria mice

“…Of these possibilities, the last one is less likely, because only a small fraction (o10%) of recombinant AAV genome was reportedly integrated into the mouse hepatocytes. 23 If there is an androgen-dependent mechanism to retain the AAV genome in an episomal state in the liver, lack of such machinery would allow gradual loss of the vector DNA in females, thereby transgene-derived PAH activity would descend over time as we observed. Other possibilities accounting for the lower therapeutic efficacy include transcriptional silencing and an immune response against AAV-transduced hepatocytes, although the latter is unlikely to occur only in female mice.…”

Potential of AAV vectors in the treatment of metabolic disease

“…Studies in adult mice have shown that partial hepatectomy, which is associated with a burst of hepatocellular proliferation, leads to rapid loss of episomal vector genomes. [14][15][16] Essentially the same phenomenon is seen following vector delivery to neonatal mice, where high rates of hepatocellular proliferation result in almost complete clearance of episomal vector genomes within two doublings of liver mass occurring within the first 1-2 weeks of life. 17,18 A stable basal level of transgene expression, probably reflecting vector integration, persists thereafter in up to 8% of hepatocytes depending on the vector dose used.…”

“…Additionally, the theoretical risk of insertional mutagenesis is reduced, as the majority of transduction events following AAV-mediated gene transfer result from the formation of transcriptionally active episomes rather than vector integration. 14,32 Recent reports, however, linking tumor formation in the mouse liver to integration events are currently causing a reevaluation of theoretical assumptions. 33,34 Whether integration events are truly causative of observed tumors remains controversial as the observation of tumor formation is inconsistent across multiple studies.…”

Gene Therapy Progress and Prospects: Recombinant adeno-associated virus (rAAV) vectors

“…The delivery of rAAV2 vectors to the liver has also been demonstrated to be very efficient. [30][31][32][33][34][35] rAAV2-based gene delivery to muscle and liver has been shown to be quite effective for delivery of secreted proteins, such as factor IX and alpha-1 antitrypsin 34,35 (Figure 2). …”