The AAV capsid can influence the epigenetic marking of rAAV delivered episomal genomes in a species dependent manner

• Published in: Nature communications Vol. 14; no. 1; pp. 2448 - 11
• Main Authors: Gonzalez-Sandoval, Adriana, Pekrun, Katja, Tsuji, Shinnosuke, Zhang, Feijie, Hung, King L., Chang, Howard Y., Kay, Mark A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.04.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/107; 13/109; 38; 38/44; 42; 42/44; 45; 631/208/176; 631/326/596/2561; 631/45/612/100/2285; 631/61/201; 631/61/2300/1514; Amino acids; Animals; Capsid - metabolism; Capsid protein; Capsid Proteins - genetics; Capsid Proteins - metabolism; Capsids; Chromatin; Chromatin - genetics; Chromatin - metabolism; Deoxyribonucleic acid; Dependovirus - metabolism; Discordance; DNA; Epigenesis, Genetic; Epigenetics; Gene therapy; Genetic Vectors - genetics; Genomes; Histone H3; Histones; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Nuclear transport; Proteins; Science; Science (multidisciplinary); Species; Transduction; Transduction, Genetic; Uncoating; Vectors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38106-3

Recombinant adeno-associated viral vectors (rAAVs) are among the most commonly used vehicles for in vivo based gene therapies. However, it is hard to predict which AAV capsid will provide the most robust expression in human subjects due to the observed discordance in vector-mediated transduction between species. In our study, we use a primate specific capsid, AAV-LK03, to demonstrate that the limitation of this capsid towards transduction of mouse cells is unrelated to cell entry and nuclear transport but rather due to depleted histone H3 chemical modifications related to active transcription, namely H3K4me3 and H3K27ac, on the vector DNA itself. A single-amino acid insertion into the AAV-LK03 capsid enables efficient transduction and the accumulation of active-related epigenetic marks on the vector chromatin in mouse without compromising transduction efficiency in human cells. Our study suggests that the capsid protein itself is involved in driving the epigenetic status of the vector genome, most likely during the process of uncoating. Programming viral chromatin states by capsid design may enable facile DNA transduction between vector and host species and ultimately lead to rational selection of AAV capsids for use in humans. rAAV vectors vary in their effectiveness between species, making it difficult to predict clinical outcomes. Here authors show that AAV capsid proteins influence the vector epigenomic state in cells, and that a single amino acid change in the vector can alter the vector epigenome and hence transgene expression levels between species.