The next step in gene delivery: Molecular engineering of adeno-associated virus serotypes

Wang, Jinhui; Faust, Susan M.; Rabinowitz, Joseph E.

doi:10.1016/j.yjmcc.2010.10.017

Cited by 63 publications

(46 citation statements)

References 146 publications

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“…Constitutive binding of NF-kB to IkBa was facilitated by the generation of a mutant IkBa construct that cannot be phosphorylated by the upstream kinase IKKb due to exchange of the inhibitory phosphorylation sites serine 32 and serine 36 to alanine. Potential adverse effects caused by viral-induced inflammation were circumvented by the use of AAV2, which does not cause adverse local immune responses in comparison with, for example, adenovirus (40,41). A study performed by Zhang et al (14) has comprehensively assessed the role of the IKKb/ NF-kB pathway in the control of energy metabolism by elegantly combining central gene knockout and adenoviral manipulation of this pathway.…”

Section: Discussionmentioning

confidence: 99%

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

et al. 2015

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Metabolic inflammation in the central nervous system might be causative for the development of overnutritioninduced metabolic syndrome and related disorders, such as obesity, leptin and insulin resistance, and type 2 diabetes. Here we investigated whether nutritive and genetic inhibition of the central IkB kinase b (IKKb)/nuclear factor-kB (NF-kB) pathway in diet-induced obese (DIO) and leptin-deficient mice improves these metabolic impairments. A known prominent inhibitor of IKKb/NF-kB signaling is the dietary flavonoid butein. We initially determined that oral, intraperitoneal, and intracerebroventricular administration of this flavonoid improved glucose tolerance and hypothalamic insulin signaling. The dosedependent glucose-lowering capacity was profound regardless of whether obesity was caused by leptin deficiency or high-fat diet (HFD). To confirm the apparent central role of IKKb/NF-kB signaling in the control of glucose and energy homeostasis, we genetically inhibited this pathway in neurons of the arcuate nucleus, one key center for control of energy homeostasis, via specific adeno-associated virus serotype 2-mediated overexpression of IkBa, which inhibits NF-kB nuclear translocation. This treatment attenuated HFD-induced body weight gain, body fat mass accumulation, increased energy expenditure, and reduced arcuate suppressor of cytokine signaling 3 expression, indicative for enhanced leptin signaling. These results reinforce a specific role of central proinflammatory IKKb/NF-kB signaling in the development and potential treatment of DIO-induced comorbidities.

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Section: Discussionmentioning

confidence: 99%

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

et al. 2015

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“…[42][43][44][45][46] Although further modifications of the AAV-vector surface (educated guess or library-based approaches) could extend the tropism of gene transfer, for example, to vessels or increase specificity, AAV9 vectors still remain the vector of choice for systemic cardiac gene transfer in rodents. 21,47 Because AAV9 vectors enable a highly efficient but not specific cardiac gene transfer, specificity of expression can be increased using a tissue-specific promoter or an appropriate microRNA-target site into the AAV-genome. 48,49 The role of a tissue-specific promoter is increasingly acknowledged in the development of gene therapy [50][51][52] but has also been demonstrated for the cardiac-specific expression of fluorescent proteins.…”

Section: Delivery Of Genetically Encoded Ca 2+ Sensors To Cardiac Myomentioning

confidence: 99%

Genetically Encoded Ca ²⁺ Indicators in Cardiac Myocytes

Kaestner

Scholz

Tian

et al. 2014

Circulation Research

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“…In addition to these limitations, the host cell also exploits various cellular components as barriers to productive AAV infection, including the critical steps required for viral trafficking (e.g., cell surface uptake, cytoplasmic trafficking, endosomal escape, nuclear entry, etc.) (53). Better understanding of the AAV cellular trafficking will advance our knowledge of AAV biology and facilitate the development of enhanced AAV vectors.…”

mentioning

confidence: 99%

Cytoplasmic Trafficking, Endosomal Escape, and Perinuclear Accumulation of Adeno-Associated Virus Type 2 Particles Are Facilitated by Microtubule Network

Xiao

Samulski

2012

J Virol

119

110

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Understanding adeno-associated virus (AAV) trafficking is critical to advance our knowledge of AAV biology and exploit novel aspects of vector development. Similar to the case for most DNA viruses, after receptor binding and entry, AAV traverses the cytoplasm and deposits the viral genome in the cell nucleus. In this study, we examined the role of the microtubule (MT) network in productive AAV infection. Using pharmacological reagents (e.g., nocodazole), live-cell imaging, and flow cytometry analysis, we demonstrated that AAV type 2 (AAV2) transduction was reduced by at least 2-fold in the absence of the MT network. Cell surface attachment and viral internalization were not dependent on an intact MT network. In treated cells at 2 h postinfection, quantitative three-dimensional (3D) microscopy determined a reproducible difference in number of intracellular particles associated with the nuclear membrane or the nucleus compared to that for controls (6 to 7% versus 26 to 30%, respectively). Confocal microscopy analysis demonstrated a direct association of virions with MTs, further supporting a critical role in AAV infection. To investigate the underling mechanisms, we employed single-particle tracking (SPT) to monitor the viral movement in real time. Surprisingly, unlike other DNA viruses (e.g., adenovirus [Ad] and herpes simplex virus [HSV]) that display bidirectional motion on MTs, AAV2 displays only unidirectional movement on MTs toward the nuclei, with peak instantaneous velocities at 1.5 to 3.5 μm/s. This rapid and unidirectional motion on MTs lasts for about 5 to 10 s and results in AAV particles migrating more than 10 μm in the cytoplasm reaching the nucleus very efficiently. Furthermore, electron microscopy analysis determined that, unlike Ad and HSV, AAV2 particles were transported on MTs within membranous compartments, and surprisingly, the acidification of AAV2-containing endosomes was delayed by the disruption of MTs. These findings together suggest an as-yet-undescribed model in which after internalization, AAV2 exploits MTs for rapid cytoplasmic trafficking in endosomal compartments unidirectionally toward the perinuclear region, where most acidification events for viral escape take place.

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The next step in gene delivery: Molecular engineering of adeno-associated virus serotypes

Cited by 63 publications

References 146 publications

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

Genetically Encoded Ca ²⁺ Indicators in Cardiac Myocytes

Cytoplasmic Trafficking, Endosomal Escape, and Perinuclear Accumulation of Adeno-Associated Virus Type 2 Particles Are Facilitated by Microtubule Network

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The next step in gene delivery: Molecular engineering of adeno-associated virus serotypes

Cited by 63 publications

References 146 publications

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

Central Inhibition of IKKβ/NF-κB Signaling Attenuates High-Fat Diet–Induced Obesity and Glucose Intolerance

Genetically Encoded Ca 2+ Indicators in Cardiac Myocytes

Cytoplasmic Trafficking, Endosomal Escape, and Perinuclear Accumulation of Adeno-Associated Virus Type 2 Particles Are Facilitated by Microtubule Network

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Genetically Encoded Ca ²⁺ Indicators in Cardiac Myocytes