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Title: Syngeneic AAV pseudo-particles potentiate gene transduction of AAV vectors

item WANG, QIZHAO - School Of Biomedical Sciences, Huaqiao University
item DONG, BIAO - Temple University
item POKINIEWSKI, KATIE - Temple University
item Firrman, Jenni
item WU, ZHONGREN - Temple University
item CHIN, MARIO - School Of Biomedical Sciences, Huaqiao University
item CHEN, XIONGWEN - Temple University
item Liu, Linshu
item XU, RUIAN - School Of Biomedical Sciences, Huaqiao University
item DIAO, YONG - School Of Biomedical Sciences, Huaqiao University
item XIAO, WEIDONG - School Of Biomedical Sciences, Huaqiao University

Submitted to: Molecular Therapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/16/2016
Publication Date: 3/17/2017
Citation: Wang, Q., Dong, B., Pokiniewski, K.A., Firrman, J., Wu, Z., Chin, M.P., Chen, X., Liu, L.S., Xu, R., Diao, Y., Xiao, W. 2017. Syngeneic AAV pseudo-particles potentiate gene transduction of AAV vectors. Molecular Therapy. doi: 10.1016/j.omtm.2016.12.004. PMCID: PMC5363323.

Interpretive Summary: Gene therapy is a type of treatment for disease that works by delivering a gene into a human cell. Gene therapy using a small, non-toxic virus called Adeno-Associated Virus (AAV) as a vehicle to deliver the gene into the cell has produced promising results. However, preparing AAV in large batches is difficult, and often results in the formation of not only AAV but other viral particles that may contain either some DNA or no DNA. At first it was thought that these extra particles were not useful and were considered a contaminating byproduct. However, this paper demonstrates that these other particles may have function. Experiments both in tissue culture and mice demonstrated that when these other viral particles were used with AAV, the gene expression was enhanced. These results indicate these other particles may serve a purpose and be useful in human gene therapy.

Technical Abstract: Gene delivery vectors based on adeno-associated virus (AAV) have emerged as safe and efficient therapeutic platform for numerous diseases. Excessive empty particles were generated as impurities during AAV vector production, but their effects on clinical outcome of AAV gene therapy are unclear. Here, we generated three empty AAV particles, syngeneic AAV pseudo-vector (sAAV) (partially empty particles and distinct from the bona fide full AAV vector), allogeneic AAV pseudo-vector (aAAV) (partially empty particles but from AAV vector with a different genome), and null AAV pseudo-vector (nAAV) (completely empty particles without any DNA). We found that the DNA component in the pseudo-vectors indicated a key role in dictating the effects on AAV transduction. Different hemophilia A models showed 9-fold (9X) excess of sAAV8 increased AAV8 transduction both in vivo and in vitro. However, these effects were absent when the AAV8 vectors were co-transduced with nAAV8 and aAAV8. Partial genomes of sAAV annealing to the full length AAV genomes is the potential underlying mechanism which facilitates the second strand DNA synthesis, thereby increasing the AAV transduction. Taken together, our results showed that formulation of syngeneic AAV pseudo-vectors in the final AAV vectors will enhance the efficacy of gene transfer after systemic vector delivery.