Adeno-Associated Virus: The Naturally Occurring Virus Versus the Recombinant Vector

Srivastava, Arun

doi:10.1089/hum.2015.29017.asr

Cited by 21 publications

(18 citation statements)

References 42 publications

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“…Although we hypothesized that such a wide range of donor variation is due to different levels of expression of the putative receptors and/ or co-receptors on these cells, we were able to achieve significant increase in the transduction efficiency of both AAV2 and AAV6 vectors using site-directed mutagenesis of surface-exposed tyrosine (Y) residues. We therefore wished to examine whether the transduction efficiency of AAV6 vectors could be further improved by additional capsid modifications involving mutagenesis of surface-exposed serine (S) and threonine (T) residues, and various permutations and combinations thereof 22 . To this end, a number of such mutant capsids were generated, and self-complementary AAV6 (scAAV6) vectors containing a chicken beta actin promoter/CMV enhancer driving an enhanced green fluorescence protein gene (CBAp-EGFP) were produced as previously reported 23 .…”

Section: Resultsmentioning

confidence: 99%

High-Efficiency Transduction of Primary Human Hematopoietic Stem/Progenitor Cells By AAV6 Vectors: strategies for Overcoming Donor-Variation and Implications in Genome Editing

Chen

Bhukhai

Yin

et al. 2016

Blood

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We have reported that of the 10 commonly used AAV serotype vectors, AAV6 is the most efficient in transducing primary human hematopoietic stem/progenitor cells (HSPCs). However, the transduction efficiency of the wild-type (WT) AAV6 vector varies greatly in HSPCs from different donors. Here we report two distinct strategies to further increase the transduction efficiency in HSPCs from donors that are transduced less efficiently with the WT AAV6 vectors. The first strategy involved modifications of the viral capsid proteins where specific surface-exposed tyrosine (Y) and threonine (T) residues were mutagenized to generate a triple-mutant (Y705 + Y731F + T492V) AAV6 vector. The second strategy involved the use of ex vivo transduction at high cell density. The combined use of these strategies resulted in transduction efficiency exceeding ~90% in HSPCs at significantly reduced vector doses. Our studies have significant implications in the optimal use of capsid-optimized AAV6 vectors in genome editing in HSPCs.Genetically-modified autologous hematopoietic stem/progenitor cells (HSPCs) transplantation is the most promising therapeutic strategy to treat inherited genetic diseases, such as β -globin disorders 1 , leukodystrophies 2,3 , severe combined immunodeficiency 4 , Wiskott-Aldrich syndrome 5 , as well as acquired diseases such as AIDS 6 . Recent remarkable progress in genome editing tools include zinc-finger nucleases (ZFNs), transcription activator like effector nucleases (TALENs), and the RNA-guided clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas9 endonucleases. These targeted nucleases further expand the application of ex vivo editing of therapeutic genes into patient HSPCs 7 . Most of these methods require the delivery of extracellular DNA into HSPCs, the efficiency of which is frequently sub-optimal. In the present study, we describe a novel, adeno-associated virus (AAV) vector-based DNA delivery strategy to overcome the current drawbacks that limit the clinical use of HSPCs gene editing methods.The current drawbacks of HSPCs gene editing using viral methods such as chimeric adenoviral vectors, retroviral vectors, or integrase-defective lentiviral vectors (IDLV) include inefficient gene delivery, cytotoxicity, or DNA insertion. For example in a phase I/II clinical trial, a self-inactivating lentiviral vector achieved genetic

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Section: Resultsmentioning

confidence: 99%

High-Efficiency Transduction of Primary Human Hematopoietic Stem/Progenitor Cells By AAV6 Vectors: strategies for Overcoming Donor-Variation and Implications in Genome Editing

Chen

Bhukhai

Yin

et al. 2016

Blood

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“…The well-established safety of AAV vectors in 162 Phase I/II clinical trials in humans to date, and clinical efficacy in at least 6 human diseases, essentially ensures that with the availability of a vast repertoire of AAV serotype vectors, which is certainly likely to expand, the coming decades will witness their successful use in curing a wide variety of human diseases, both genetic and acquired. Furthermore, the future outlook appears even more optimistic, given the currently ongoing efforts to design and optimize novel AAV serotype vectors capable of targeting specific tissues and organs [86]. However, it is important to emphasize that efforts to pursue the basic molecular biology of AAV in general, and AAV vectors in particular, must also continue, which will, most assuredly, continue to pay rich dividends.…”

Section: Discussionmentioning

confidence: 99%

In vivo tissue-tropism of adeno-associated viral vectors

Srivastava

2016

Current Opinion in Virology

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276

182

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In this review, a brief account of the historical perspective of the discovery of the first cellular receptor and co-receptor of the prototype adeno-associated virus serotype 2 (AAV2) will be presented. The Subsequent discovery of a number of AAV serotypes, and attempts to identify the cellular receptors and co-receptors for these serotype vectors has had significant implications in their use in human gene therapy. As additional AAV serotypes are discovered and isolated, a detailed understanding of their tropism is certainly likely to play a key role in all future studies, both basic science as well as clinical.

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“…Here we show the first preclinical evidence that sustained preproSST expression initiated after stable seizures are evoked in experimental TLE is anticonvulsant in a subset of rats. The opportunity to achieve complete seizure-free state with superior responder rates in epilepsy gene therapy intervention also supports development and optimization of better gene delivery strategies like AAV capsid shuffling (Gray et al, 2010), the use of capsid mutated (Petrs-Silva et al, 2009;Zhong et al, 2008;Zhong et al, 2007) and self-complementary AAV vectors(McCarty et al, 2003;McCarty, Monahan, & Samulski, 2001) that can possibly enhance transgene expression and provide superior transduction (Srivastava, 2016). Future studies might also test whether the use of promoters to drive expression selectively in specific cell types might improve responder rates (Nathanson et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated viral vector-mediated preprosomatostatin expression suppresses induced seizures in kindled rats

et al. 2017

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Somatostatin is expressed widely in the hippocampus and notably in hilar GABAergic neurons that are vulnerable to seizure neuropathology in chronic temporal lobe epilepsy. We previously demonstrated that sustained bilateral preprosomatostatin (preproSST) expression in the hippocampus prevents the development of generalized seizures in the amygdala kindling model of temporal lobe epilepsy. Here we tested whether sustained preproSST expression is anticonvulsant in rats already kindled to high-grade seizures. Rats were kindled until they exhibited 3 consecutive Racine Grade 5 seizures before adeno-associated virus serotype 5 (AAV5) vector driving either eGFP (AAV5-CBa-eGFP) or preproSST and eGFP (AAV5-CBa-preproSST-eGFP) expression was injected bilaterally into the hippocampal dentate gyrus and CA1 region. Retested 3 weeks later, rats that received control vector (AAV5-CBa-eGFP) continued to exhibit high-grade seizures whereas 6/13 rats that received preproSST vector (AAV5-CBa-preproSST-eGFP) were seizure-free. Of these rats, 5/6 remained seizure-free after repeated stimulation sessions and when the stimulation current was increased. These results suggest that vector-mediated expression of preproSST may be a viable therapeutic strategy for temporal lobe epilepsy.

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Adeno-Associated Virus: The Naturally Occurring Virus Versus the Recombinant Vector

Cited by 21 publications

References 42 publications

High-Efficiency Transduction of Primary Human Hematopoietic Stem/Progenitor Cells By AAV6 Vectors: strategies for Overcoming Donor-Variation and Implications in Genome Editing

High-Efficiency Transduction of Primary Human Hematopoietic Stem/Progenitor Cells By AAV6 Vectors: strategies for Overcoming Donor-Variation and Implications in Genome Editing

In vivo tissue-tropism of adeno-associated viral vectors

Adeno-associated viral vector-mediated preprosomatostatin expression suppresses induced seizures in kindled rats

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