Designer Gene Delivery Vectors: Molecular Engineering and Evolution of Adeno-Associated Viral Vectors for Enhanced Gene Transfer
Inchan Kwon,David V. Schaffer +1 more
TLDR
Molecular engineering and directed evolution of AAV vectors offer promise for generating ‘designer’ gene delivery vectors with enhanced properties, particularly those based on AAV2, the best characterized AAV serotype.Abstract:
Gene delivery vectors based on adeno-associated virus (AAV) are highly promising due to several desirable features of this parent virus, including a lack of pathogenicity, efficient infection of dividing and non-dividing cells, and sustained maintenance of the viral genome. However, several problems should be addressed to enhance the utility of AAV vectors, particularly those based on AAV2, the best characterized AAV serotype. First, altering viral tropism would be advantageous for broadening its utility in various tissue or cell types. In response to this need, vector pseudotyping, mosaic capsids, and targeting ligand insertion into the capsid have shown promise for altering AAV specificity. In addition, library selection and directed evolution have recently emerged as promising approaches to modulate AAV tropism despite limited knowledge of viral structure–function relationships. Second, pre-existing immunity to AAV must be addressed for successful clinical application of AAV vectors. “Shielding” polymers, site-directed mutagenesis, and alternative AAV serotypes have shown success in avoiding immune neutralization. Furthermore, directed evolution of the AAV capsid is a high throughput approach that has yielded vectors with substantial resistance to neutralizing antibodies. Molecular engineering and directed evolution of AAV vectors therefore offer promise for generating ‘designer’ gene delivery vectors with enhanced properties.read more
Citations
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Journal ArticleDOI
In Vitro and In Vivo Gene Therapy Vector Evolution via Multispecies Interbreeding and Retargeting of Adeno-Associated Viruses
Dirk Grimm,Joyce S. Lee,Lora Wang,Tushar J. Desai,Bassel Akache,Theresa A. Storm,Mark A. Kay +6 more
TL;DR: This study validates DNA family shuffling and viral peptide display as two powerful and compatible approaches to the molecular evolution of novel AAV vectors for human gene therapy applications.
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High-efficiency Transduction of the Mouse Retina by Tyrosine-mutant AAV Serotype Vectors
Hilda Petrs-Silva,Astra Dinculescu,Qiuhong Li,Seok-Hong Min,Vince A. Chiodo,Jijing Pang,Li Zhong,Sergei Zolotukhin,Arun Srivastava,Alfred S. Lewin,William W. Hauswirth +10 more
TL;DR: Efficient transduction of the ganglion cell layer by AAV serotype 8 or 9 mutant vectors is shown, thus providing additional tools besides AAV2 for targeting these cells, which have a great potential for future therapeutic applications for retinal degenerations and ocular neovascular diseases.
Journal ArticleDOI
Recombinant Adeno-associated Virus Transduction and Integration
TL;DR: The current understanding of the mechanisms and rate-limiting steps involved in rAAV transduction is described, which suggest that nondividing cells tend to be most stably transduced.
Journal ArticleDOI
Efficient gene delivery and selective transduction of glial cells in the mammalian brain by AAV serotypes isolated from nonhuman primates.
TL;DR: Glial transduction was observed using rh43 and AAV8, driven by the glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) promoters, expanding the utility of AAV for modeling and treating diseases involving glial cell pathology.
Journal ArticleDOI
A survey of ex vivo/in vitro transduction efficiency of mammalian primary cells and cell lines with Nine natural adeno-associated virus (AAV1-9) and one engineered adeno-associated virus serotype
Brian L. Ellis,Matthew L. Hirsch,Jenny C. Barker,Jon P. Connelly,Robert J. Steininger,Matthew H. Porteus +5 more
TL;DR: The transduction efficiency of ten different AAV serotypes in thirty-four different mammalian cell lines and primary cell types is described to provide an important and unique resource for investigators who use AAV as an ex vivo gene delivery vector or who work with cells that are difficult to transfect.
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