Gene Therapy Progress and Prospects: Viral trafficking during infection

Campbell, E. M.; Hope, Thomas J.

doi:10.1038/sj.gt.3302585

Cited by 39 publications

(27 citation statements)

References 35 publications

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“…Disruption of the inner limiting membrane caused by mild proteolytic digestion, 72 by structural changes of the Müller cell endfeet, 73 by laser pretreatment, 74 or by retinal degeneration 72 allow for enhanced AAV transduction of outer retinal cells after their intravitreal delivery. Moreover, nuclear uptake, capsid uncoating, and second-strand DNA synthesis following receptor binding are major rate-limiting steps in AAV transduction [75][76][77][78] that need to be investigated.…”

Section: Aav2 Vectors Reverse Diabetic Retinal Alterations N Díaz-lezmentioning

confidence: 99%

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Díaz‐Lezama

Adán‐Castro

et al. 2016

Laboratory Investigation

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Adeno-associated virus (AAV) vector-mediated delivery of inhibitors of blood-retinal barrier breakdown (BRBB) offers promise for the treatment of diabetic macular edema. Here, we demonstrated a reversal of blood-retinal barrier pathology mediated by AAV type 2 (AAV2) vectors encoding vasoinhibin or soluble VEGF receptor 1 (sFlt-1) when administered intravitreally to diabetic rats. Efficacy and safety of the AAV2 vasoinhibin vector were tested by monitoring its effect on diabetes-induced changes in the retinal vascular bed and thickness, and in the electroretinogram (ERG). Also, the transduction of AAV2 vectors and expression of AAV2 receptors and co-receptors were compared between the diabetic and the non-diabetic rat retinas. AAV2 vasoinhibin or AAV2 sFlt-1 vectors were injected intravitreally before or after enhanced BRBB due to diabetes induced by streptozotocin. The BRBB was examined by the Evans blue method, the vascular bed by fluorescein angiography, expression of the AAV2 EGFP reporter vector by confocal microscopy, and the AAV2 genome, expression of transgenes, receptors, and co-receptors by quantitative PCR. AAV2 vasoinhibin and sFlt-1 vectors inhibited the diabetes-mediated increase in BRBB when injected after, but not before, diabetes was induced. The AAV2 vasoinhibin vector decreased retinal microvascular abnormalities and the diabetes-induced reduction of the B-wave of the ERG, but it had no effect in non-diabetic controls. Also, retinal thickness was not altered by diabetes or by the AAV2 vasoinhibin vector. The AAV2 genome, vasoinhibin and sFlt-1 transgenes, and EGFP levels were higher in the retinas from diabetic rats and were associated with an elevated expression of AAV2 receptors (syndecan, glypican, and perlecan) and co-receptors (fibroblast growth factor receptor 1, αvβ5 integrin, and hepatocyte growth factor receptor). We conclude that retinal transduction and efficacy of AAV2 vectors are enhanced in diabetes, possibly due to their elevated cell entry. AAV2 vectors encoding vasoinhibin and sFlt-1 may be desirable gene therapeutics to target diabetic retinopathy and macular edema.

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Section: Aav2 Vectors Reverse Diabetic Retinal Alterations N Díaz-lezmentioning

confidence: 99%

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Díaz‐Lezama

Adán‐Castro

et al. 2016

Laboratory Investigation

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“…Some studies in this area have also suggested that the rate of intracellular processing and the process of uncoating of viral vectors may critically affect host immune responses toward input capsids, in the absence of new viral protein synthesis (Campbell and Hope, 2005;Ding et al, 2005).…”

Section: Adeno-associated Virus Biology and Trafficking In Host Cellsmentioning

confidence: 99%

“…The knowledge of the intracellular processing in these and other existing serotypes is becoming even more important with the increasing identification of new AAV serotypes (Campbell and Hope, 2005;Ding et al, 2005).…”

Section: Adeno-associated Virus Biology and Trafficking In Host Cellsmentioning

confidence: 99%

A role for adeno-associated viral vectors in gene therapy

Coura

Nardi

2008

Genet. Mol. Biol.

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Gene therapy constitutes a therapeutic intervention based on modification of the genetic material of living cells, by correcting genetic defects or overexpressing therapeutic proteins. The success of gene therapy protocols depends on the availability of therapeutically suitable genes, appropriate gene delivery systems and proof of safety and efficacy. Recent advances on the development of gene delivery systems, particularly on viral vectors engineering and improved gene regulatory systems, have led to marked progress in this field. Although the available vector systems can successfully transfer genes into cells, the ideal delivery vehicle has not been found. In this context, adeno-associated virus vectors (AAV) are arising as a promising tool for a wide range of applications, due to a combination of characteristics such as lack of pathogenicity and immunogenicity, wide range of cell tropism and long-term gene expression. Since its isolation, the biological properties of the adeno-associated virus have been increasingly understood, improving our ability to manipulate and use it as a safe and efficient gene therapy vector of wide spectrum. In this work, we review the bases of gene therapy, main types of gene transfer systems and basic properties and use of AAV vectors.

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“…HIV-1 has been shown to use actin microfilaments for short-range transport at the cell and nuclear periphery, and MT motors for long-range intracellular movement (10,75,76). Confusingly, numerous non-motile tubulin-and actin-associated proteins have been identified by genomewide screens of proteins thought to contribute to efficient HIV-1 infection (77-79).…”

Section: Maps Facilitate Interaction Of Viruses With Microtubulesmentioning

confidence: 99%

Role of non-motile microtubule-associated proteins in virus trafficking

Portilho

Persson²,

Arhel

2016

Biomolecular Concepts

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Viruses are entirely dependent on their ability to infect a host cell in order to replicate. To reach their site of replication as rapidly and efficiently as possible following cell entry, many have evolved elaborate mechanisms to hijack the cellular transport machinery to propel themselves across the cytoplasm. Long-range movements have been shown to involve motor proteins along microtubules (MTs) and direct interactions between viral proteins and dynein and/or kinesin motors have been well described. Although less well-characterized, it is also becoming increasingly clear that non-motile microtubule-associated proteins (MAPs), including structural MAPs of the MAP1 and MAP2 families, and microtubule plus-end tracking proteins (+ TIPs), can also promote viral trafficking in infected cells, by mediating interaction of viruses with filaments and/or motor proteins, and modulating filament stability. Here we review our current knowledge on nonmotile MAPs, their role in the regulation of cytoskeletal dynamics and in viral trafficking during the early steps of infection.

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Gene Therapy Progress and Prospects: Viral trafficking during infection

Cited by 39 publications

References 35 publications

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

Diabetes enhances the efficacy of AAV2 vectors in the retina: therapeutic effect of AAV2 encoding vasoinhibin and soluble VEGF receptor 1

A role for adeno-associated viral vectors in gene therapy

Role of non-motile microtubule-associated proteins in virus trafficking

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