| First Author | Imre G | Year | 2023 |
| Journal | Mol Ther Methods Clin Dev | Volume | 29 |
| Pages | 145-159 | PubMed ID | 37025950 |
| Mgi Jnum | J:339460 | Mgi Id | MGI:7522572 |
| Doi | 10.1016/j.omtm.2023.03.003 | Citation | Imre G, et al. (2023) Prolonged activity of the transposase helper may raise safety concerns during DNA transposon-based gene therapy. Mol Ther Methods Clin Dev 29:145-159 |
| abstractText | DNA transposon-based gene delivery vectors represent a promising new branch of randomly integrating vector development for gene therapy. For the side-by-side evaluation of the piggyBac and Sleeping Beauty systems-the only DNA transposons currently employed in clinical trials-during therapeutic intervention, we treated the mouse model of tyrosinemia type I with liver-targeted gene delivery using both transposon vectors. For genome-wide mapping of transposon insertion sites we developed a new next-generation sequencing procedure called streptavidin-based enrichment sequencing, which allowed us to identify approximately one million integration sites for both systems. We revealed that a high proportion of piggyBac integrations are clustered in hot regions and found that they are frequently recurring at the same genomic positions among treated animals, indicating that the genome-wide distribution of Sleeping Beauty-generated integrations is closer to random. We also revealed that the piggyBac transposase protein exhibits prolonged activity, which predicts the risk of oncogenesis by generating chromosomal double-strand breaks. Safety concerns associated with prolonged transpositional activity draw attention to the importance of squeezing the active state of the transposase enzymes into a narrower time window. |
