Systemic delivery of adeno-associated viral vectors

Duan, Dongsheng

doi:10.1016/j.coviro.2016.07.006

Cited by 92 publications

(61 citation statements)

References 148 publications

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“…AAV has a broad host and cell-type tropism capable of transducing both dividing and non-dividing cells. To date, 12 AAV serotypes and > 100 variants have been identified [1,2]. Different serotype capsids have different infectivity rates in tissue and cultured cells, which depend on the primary receptor and co-receptors on the cell surface, or on the intracellular trafficking pathway itself.…”

Section: Introductionmentioning

confidence: 99%

Application of polyploid adeno-associated virus vectors for transduction enhancement and neutralizing antibody evasion

Chai

Sun

Rigsbee

et al. 2017

Journal of Controlled Release

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Adeno-associated virus (AAV) vectors have been used successfully in clinical trials for patients with hemophilia or blindness, but pre-existing neutralizing antibodies (Nab) are common in the general population and exclude many patients from clinical trials. Exploration of effective strategies to enhance AAV transduction and escape from Nab activity is still imperative. Previous studies have shown the compatibility of capsids from AAV serotypes and homology of recognition sites of AAV Nab located on different capsid subunits from one virion. In this study, we co-transfected AAV2 and AAV8 helper plasmids at different ratios (3:1, 1:1 and 1:3) to assemble haploid capsids and study both their transduction efficiency and Nab escape activity. After muscular injection, all of the haploid viruses induced higher transduction than their parental AAV vectors (2- to 9-fold over AAV2), with the highest of these being the haploid vector AAV2/8 3:1. After systemic administration, a 4-fold higher transduction in the liver was observed with haploid AAV2/8 1:3 than that with AAV8 alone. We then packaged the therapeutic factor IX cassette into haploid AAV2/8 1:3 capsids and injected them into FIX knockout mice via the tail vein. Higher FIX expression and improved phenotypic correction were achieved with the haploid AAV2/8 1:3 virus vector when compared to that of AAV8. Additionally, the haploid virus AAV2/8 1:3 was able to escape AAV2 neutralization and did not increase capsid antigen presentation capacity when compared to AAV8. To improve the Nab evasion ability of the haploid virus, we produced the triploid vector AAV2/8/9 by co-transfecting AAV2, AAV8 and AAV9 helper plasmids at a ratio of 1:1:1. After systemic administration, a 2-fold higher transduction in the liver was observed with the triploid vector AAV2/8/9 than that with AAV8. Nab analysis demonstrated that the triploid AAV2/8/9 vector was able to escape Nab activity from mouse sera immunized with parental serotypes. These results indicate that polyploid viruses might potentially acquire advantages from parental serotypes for enhancement of AAV transduction and evasion of Nab recognition without increasing capsid antigen presentation in target cells. Polyploid AAV vectors can be generated from any AAV serotype, whether natural, rational, library derived or a combination thereof, providing a novel strategy that should be explored in future clinical trials in patients with neutralizing antibodies.

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Section: Introductionmentioning

confidence: 99%

Application of polyploid adeno-associated virus vectors for transduction enhancement and neutralizing antibody evasion

Chai

Sun

Rigsbee

et al. 2017

Journal of Controlled Release

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“…Introduction of a functional copy of dystrophin into skeletal muscle of a DMD patient could theoretically be accomplished by viral or nonviral methods. Currently the preeminent candidate for virus‐ mediated gene delivery is adeno‐associated virus, which can transduce both cardiac and skeletal muscle via systemic delivery (37). However, adeno‐associated viruses (and other viral constructs) exhibit a limited packaging capacity, requiring delivery of a smaller, less functional m‐dystrophin or Cas9 to repair endogenous mutations (4‐6, 8).…”

Section: Discussionmentioning

confidence: 99%

“…can transduce both cardiac and skeletal muscle via systemic delivery (37). However, adeno-associated viruses (and other viral constructs) exhibit a limited packaging capacity, requiring delivery of a smaller, less functional m-dystrophin or Cas9 to repair endogenous mutations (4)(5)(6)8).…”

Section: Discussionmentioning

confidence: 99%

In vivo myomaker‐mediated heterologous fusion and nuclear reprogramming

2016

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Knowledge regarding cellular fusion and nuclear reprogramming may aid in cell therapy strategies for skeletal muscle diseases. An issue with cell therapy approaches to restore dystrophin expression in muscular dystrophy is obtaining a sufficient quantity of cells that normally fuse with muscle. Here we conferred fusogenic activity without transdifferentiation to multiple non-muscle cell types and tested dystrophin restoration in mouse models of muscular dystrophy. We previously demonstrated that myomaker, a skeletal muscle-specific transmembrane protein necessary for myoblast fusion, is sufficient to fuse 10T 1/2 fibroblasts to myoblasts in vitro. Whether myomaker-mediated heterologous fusion is functional in vivo and whether the newly introduced nonmuscle nuclei undergoes nuclear reprogramming has not been investigated. We showed that mesenchymal stromal cells, cortical bone stem cells, and tail-tip fibroblasts fuse to skeletal muscle when they express myomaker. These cells restored dystrophin expression in a fraction of dystrophin-deficient myotubes after fusion in vitro. However, dystrophin restoration was not detected in vivo although nuclear reprogramming of the muscle-specific myosin light chain promoter did occur. Despite the lack of detectable dystrophin reprogramming by immunostaining, this study indicated that myomaker could be used in nonmuscle cells to induce fusion with muscle in vivo, thereby providing a platform to deliver therapeutic material.-Mitani, Y., Vagnozzi, R. J., Millay, D. P. In vivo myomaker-mediated heterologous fusion and nuclear reprogramming.

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“…An alternative to these "pre-DNA delivery" selectivity procedures is to use cell-type-and cell-state-unspecific viral or non-viral DNA delivery systems (Duan, 2016;Wong et al, 2016), and work out the cell specificity post-delivery by exploring unique genetic properties of the target cell. The transcriptional program of any given cell reflects, at the most basic level, a unique combination of binary on/off states of the regulatory elements (REs) present in the genome.…”

Section: Introductionmentioning

confidence: 99%

The intersectional genetics landscape for human

Macedo

Gontijo

2019

Preprint

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The human body is made up of hundreds, perhaps thousands of cell types and states, most of which are currently inaccessible genetically. Genetic accessibility carries significant diagnostic and therapeutic potential by allowing the selective delivery of genetic messages or cures to cells. Research in model organisms has shown that single regulatory element (RE) activities are seldom cell type specific, limiting their usage in genetic systems designed to restrict gene expression posteriorly to their delivery to cells. Intersectional genetic approaches can theoretically increase the number of genetically accessible cells, but the scope and safety of these approaches to human have not been systematically assessed due primarily to the lack of suitable thorough RE activity databases and methods to explore them. A typical intersectional method acts like an AND logic gate by converting the input of two or more active REs into a single synthetic output, which becomes unique for that cell. Here, we systematically assessed the intersectional genetics landscape of human using a curated subset of cells from a large RE usage atlas obtained by Cap Analysis of Gene Expression sequencing (CAGE-seq) of thousands of primary and cancer cells (the FANTOM5 consortium atlas). We developed the heuristics and algorithms to retrieve AND gate intersections and quality-rank them intra-and interindividually.We find that >90% of the 154 primary cell types surveyed can be distinguished from each other with as little as 3 to 4 active REs, with quantifiable safety and robustness. We call these minimal intersections of active REs with cell-type diagnostic potential "Versatile Entry Codes" (VEnCodes). Each of the 158 cancer cell types surveyed could also be distinguished from the healthy primary cell types with small VEnCodes, most of which were highly robust to intra-and interindividual variation. Finally, we provide methods for the cross-validation of CAGE-seq-derived VEnCodes and for the extraction of VEnCodes from pooled single cell sequencing data. Our work provides a systematic view of the intersectional genetics landscape in human and demonstrates the potential of these approaches for future gene delivery technologies in human.

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Systemic delivery of adeno-associated viral vectors

Cited by 92 publications

References 148 publications

Application of polyploid adeno-associated virus vectors for transduction enhancement and neutralizing antibody evasion

Application of polyploid adeno-associated virus vectors for transduction enhancement and neutralizing antibody evasion

In vivo myomaker‐mediated heterologous fusion and nuclear reprogramming

The intersectional genetics landscape for human

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