Cell-penetrating peptides enhance the transduction of adeno-associated virus serotype 9 in the central nervous system

Yuan Meng; Dong Sun; Yiyan Qin; Xiaoyi Dong; Guangzuo Luo; Ying Liu

doi:10.1016/j.omtm.2021.02.019

Cell-penetrating peptides enhance the transduction of adeno-associated virus serotype 9 in the central nervous system

Mol Ther Methods Clin Dev. 2021 Feb 27:21:28-41. doi: 10.1016/j.omtm.2021.02.019. eCollection 2021 Jun 11.

Authors

Yuan Meng¹, Dong Sun², Yiyan Qin², Xiaoyi Dong², Guangzuo Luo², Ying Liu¹

Affiliations

¹ Department of Biochemistry and Molecular Biology, China Medical University, Shenyang 110122, China.
² Institute of Translational Medicine, China Medical University, Shenyang 110122, China.

Abstract

Recombinant adeno-associated viruses (rAAVs) have been widely used in the gene therapy field for decades. However, because of the challenge of effectively delivering rAAV vectors through the blood-brain barrier (BBB), their applications for treatment of central nervous system (CNS) diseases are quite limited. In this study, we found that several cell-penetrating peptides (CPPs) can significantly enhance the in vitro transduction efficiency of AAV serotype 9 (AAV9), a promising AAV vector for treatment of CNS diseases, the best of which was the LAH4 peptide. The enhancement of AAV9 transduction by LAH4 relied on binding of the AAV9 capsid to the peptide. Furthermore, we demonstrated that the LAH4 peptide increased the AAV9 transduction in the CNS in vitro and in vivo after systemic administration. Taken together, our results suggest that CPP peptides can interact directly with AAV9 and increase the ability of this AAV vector to cross the BBB, which further induces higher expression of target genes in the brain. Our study will help to improve the applications of AAV gene delivery vectors for the treatment of CNS diseases.

Keywords: adeno-associated virus serotype 9; blood-brain barrier; cell-penetrating peptides; central nervous system.