Anti-apoptotic gene therapy prolongs survival of corneal endothelial cells during storage

Fuchsluger, Thomas Armin; Jurkunas, Ula V.; Kazlauskas, Andrius; Dana, Reza

doi:10.1038/gt.2011.20

Cited by 55 publications

(45 citation statements)

References 33 publications

(41 reference statements)

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“…Previous studies demonstrated that Bcl-xl was down-regulated in ECs apoptosis induced by Ang II (11), endostatin (35), hypoxia (36) and hypoxia/reoxygenation (25) . To the contrary, over-expression of Bcl-xl was able to protect ECs from apoptosis mediated by DNA damaging agent and pro-inflammatory cytokines (37). Identifying the factors that regulate Bcl-xl levels is of paramount importance for better maintaining ECs viability and developing more effective therapies for atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA let-7c inhibits Bcl-xl expression and regulates ox-LDL-induced endothelial apoptosis

Qin¹,

Xiao²,

Liang³

et al. 2012

BMB Reports

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Section: Discussionmentioning

confidence: 99%

MicroRNA let-7c inhibits Bcl-xl expression and regulates ox-LDL-induced endothelial apoptosis

Qin¹,

Xiao²,

Liang³

et al. 2012

BMB Reports

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“…Recent data, for example, suggest that the endothelium of human corneas treated with the anti-apoptotic gene p35 survives longer than untreated cells. 29 Clinical advances in gene therapy have shown that viral vectors can deliver genes safely to several tissues and the promising initial results from a number of clinical trials suggest that certain diseases may potentially be treatable. Successful delivery of therapeutic meganucleases to human corneas ex vivo was achieved here for the first time, highlighting the possibility of delivering genetic material or therapeutic molecules to the corneal endothelium using non-integrating rAAV2/1.…”

Section: Discussionmentioning

confidence: 99%

Gene transfer of integration defective anti-HSV-1 meganuclease to human corneas ex vivo

et al. 2014

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Corneal graft rejection is a major problem in chronic herpetic keratitis (HK) patients with latent infection. A new class of antiviral agents targeting latent and active forms of herpes simplex virus type 1 (HSV-1) is importantly required. Meganucleases are sequence-specific homing endonucleases capable of inducing DNA double-strand breaks. A proof-of-concept experiment has shown that tailor-made meganucleases are efficient against HSV-1 in vitro. To take this work a step forward, we hypothesized that the pre-treatment of human corneas in eye banks using meganuclease-encoding vectors will allow HK patients to receive a medicated cornea to resist the recurrence of the infection and the common graft rejection problem. However, this strategy requires efficient gene delivery to human corneal endothelium. Using recombinant adeno-associated virus, serotype 2/1 (rAAV2/1), efficient gene delivery of a reporter gene was demonstrated in human corneas ex vivo. The optimum viral dose was 3.7 × 10(11) VG with an exposure time of 1 day, followed by 6 days incubation in de-swelling medium. In addition, 12 days incubation can result in transgene expression in excess of 70%. Using similar transduction conditions, meganuclease transgene expression was detected in 39.4% of the endothelial cells after 2 weeks in culture. Reduction of the total viral load in the media and the endothelial cells of corneas infected with HSV-1 was shown. Collectively, this work provides information about the optimum conditions to deliver genetic material to the cornea, and demonstrates for the first time the expression of meganuclease in human corneas ex vivo and its antiviral activity. In conclusion, we demonstrate that the treatment of human corneas in eye banks before transplantation is a new approach to address the unmet clinical needs in corneal diseases.

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“…In this article, the most recent gene therapy applications to prevent immune-mediated corneal allograft rejection will be briefly summarised (table 1). Genetic modification of corneal tissues with the view of improving endothelial viability during storage has been published recently [7,8]. However, gene therapy for endothelial protection or for treatment of corneal diseases has been reviewed recently and will not be discussed in this review [9,10].…”

Section: Genetic Modification Of Corneal Allografts Prior To Transplamentioning

confidence: 99%

Gene Therapy Approaches to Prevent Corneal Graft Rejection: Where Do We Stand?

2013

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Cornea transplantation (penetrating keratoplasty) is the most frequently performed transplant procedure in humans. Despite advances in microsurgery and immunosuppressive treatment protocols, a significant number of corneal grafts still undergo immune-mediated allograft rejection. Topical treatment with corticosteroids is currently the gold standard and while this treatment is effective in many corneal transplant patients, it is much less effective in ‘high-risk' patients with previous episodes of neovascularisation or graft rejection. Therefore, alternative approaches such as genetic modification of donor corneas are needed to prevent corneal transplant rejection. Cornea transplantation holds the unique advantage in that gene therapy can be used to modify allografts ex vivo prior to transplantation. Many preclinical studies using local (and systemic) gene transfer have been performed to date and many different gene transfer vehicles (gene therapy vectors) and therapeutic strategies (immunomodulatory or graft-protective) have been investigated to prevent corneal allograft rejection. The most recent gene therapy applications to prevent corneal allograft rejection will be reviewed in this article. Moreover, it will be discussed why the development of clinical trials for the genetic modification of corneal grafts prior to transplantation is lagging behind of those for the treatment of inherited retinal diseases.

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Anti-apoptotic gene therapy prolongs survival of corneal endothelial cells during storage

Cited by 55 publications

References 33 publications

MicroRNA let-7c inhibits Bcl-xl expression and regulates ox-LDL-induced endothelial apoptosis

MicroRNA let-7c inhibits Bcl-xl expression and regulates ox-LDL-induced endothelial apoptosis

Gene transfer of integration defective anti-HSV-1 meganuclease to human corneas ex vivo

Gene Therapy Approaches to Prevent Corneal Graft Rejection: Where Do We Stand?

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