Affiliation:
1. Department of Infectious Diseases/Virology, Heidelberg University Hospital, BioQuant Center, Im Neuenheimer Feld, Heidelberg, Germany
2. German Center for Infection Research (DZIF) and German Center for Cardiovascular Research (DZHK), Heidelberg, Germany
Abstract
AbstractRecombinant adeno-associated viruses (AAV) are under intensive investigation in numerous clinical trials after they have emerged as a highly promising vector for human gene therapy. Best exemplifying their power and potential is the authorization of three gene therapy products based on wild-type AAV serotypes, comprising Glybera (AAV1), Luxturna (AAV2) and, most recently, Zolgensma (AAV9). Nonetheless, it has also become evident that the current AAV vector generation will require improvements in transduction potency, antibody evasion and cell/tissue specificity to allow the use of lower and safer vector doses. To this end, others and we devoted substantial previous research to the implementation and application of key technologies for engineering of next-generation viral capsids in a high-throughput ‘top-down’ or (semi-)rational ‘bottom-up’ approach. Here, we describe a set of recent complementary strategies to enhance features of AAV vectors that act on the level of the recombinant cargo. As examples that illustrate the innovative and synergistic concepts that have been reported lately, we highlight (i) novel synthetic enhancers/promoters that provide an unprecedented degree of AAV tissue specificity, (ii) pioneering genetic circuit designs that harness biological (microRNAs) or physical (light) triggers as regulators of AAV gene expression and (iii) new insights into the role of AAV DNA structures on vector genome stability, integrity and functionality. Combined with ongoing capsid engineering and selection efforts, these and other state-of-the-art innovations and investigations promise to accelerate the arrival of the next generation of AAV vectors and to solidify the unique role of this exciting virus in human gene therapy.
Funder
German Research Foundation
German Center for Infection Research
Publisher
Oxford University Press (OUP)
Subject
Genetics (clinical),Genetics,Molecular Biology,General Medicine
Cited by
99 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献