Adeno-associated virus vector genomes persist as episomal chromatin in primate muscle.
Recombinant adeno-associated virus (rAAV) vectors are capable of mediating long-term gene expression following administration to skeletal muscle. In rodent muscle, the vector genomes persist in the nucleus in concatemeric episomal forms. Here, we demonstrate with nonhuman primates that rAAV vectors integrate inefficiently into the chromosomes of myocytes and reside predominantly as episomal monomeric and concatemeric circles. The episomal rAAV genomes assimilate into chromatin with a typical nucleosomal pattern. The persistence of the vector genomes and gene expression for years in quiescent tissues suggests that a bona fide chromatin structure is important for episomal maintenance and transgene expression. These findings were obtained from primate muscles transduced with rAAV1 and rAAV8 vectors for up to 22 months after intramuscular delivery of 5 x 10(12) viral genomes/kg. Because of this unique context, our data, which provide important insight into in situ vector biology, are highly relevant from a clinical standpoint.
Penaud-Budloo
Magalie
M
INSERM UMR 649, CHU Hôtel Dieu, 44035 Nantes, France.
Le Guiner
Caroline
C
Nowrouzi
Ali
A
Toromanoff
Alice
A
Chérel
Yan
Y
Chenuaud
Pierre
P
Schmidt
Manfred
M
von Kalle
Christof
C
Rolling
Fabienne
F
Moullier
Philippe
P
Snyder
Richard O
RO
D000818:Animals; D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D002875:Chromosomes; D000229:Dependovirus / Q000235:genetics*; D044127:Epigenesis, Genetic; D015967:Gene Expression Regulation, Viral; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D016679:Genome, Viral; D006657:Histones / Q000378:metabolism; D008251:Macaca; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000821:virology; D009707:Nucleosomes / Q000378:metabolism; D019076:Transgenes
D002843:Chromatin; D006657:Histones; D009707:Nucleosomes