Gene Delivery to the Corneal Endothelium

George, Andrew J.T.; Arancibia‐Cárcamo, Carolina V.; Awad, H M; Comer, Richard M.; Fehevari, Zoltan; King, William J.; Kadifachi, Mohammed; Hudde, Tobias; Kerouedan-Lebossé, Christelle; Mirza, Fareed; Oral, Barbaros; Rayner, Sandra; Tan, Peng; Tay, Eugene; Larkin, Frank

doi:10.1164/ajrccm.162.supplement_3.15tac11

Cited by 33 publications

(25 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…3,4,[23][24][25] Nonviral vectors, although safe, are generally very inefficient and do not produce long-term gene expression in ocular tissues. 23,26 Adenovirus, the first vector to be systematically explored for gene transfer to the cornea, 5,27 is an efficient vector suitable for both mitotic and post-mitotic cells, but its inherent immunogenicity can limit the duration of transgene expression.…”

Section: Discussionmentioning

confidence: 99%

“…2 Ex vivo gene therapy of the donor cornea offers the prospect of improving corneal allograft survival, especially as a number of transgenes that can modulate rejection have already been identified. 3,4 Expressed transgenic proteins capable of prolonging corneal allograft survival in animal models include mammalian interleukin 10, 5 the p40 subunit of interleukin 12, 6 interleukin 4 (albeit not in all studies), [7][8][9] soluble tumour necrosis factor receptor, 10 endostatin-kringle 5 fusion protein (E-Kr5), 11 soluble CTLA4 or CTLA4-Ig constructs 12,13 and indoleamine 2,3-dioxygenase. 14 Many studies in which modulation of corneal graft rejection by gene transfer was the experimental objective have utilized non-viral or replication-deficient adenovirus vectors to transduce the cornea, so that long-term expression of the transgene was not achieved and the grafts ultimately failed.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Lentivirus-mediated gene transfer to the rat, ovine and human cornea

et al. 2007

View full text Add to dashboard Cite

Gene therapy of the cornea shows promise for modulating corneal transplant rejection but the most appropriate vector for gene transfer has yet to be determined. We investigated a lentiviral vector (LV) for its ability to transduce corneal endothelium. A lentivector expressing enhanced yellow fluorescent protein (eYFP) under the control of the Simian virus type 40 early promoter (LV-SV40-eYFP) transduced 80-90% of rat, ovine and human corneal endothelial cells as detected by fluorescence microscopy. The kinetics of gene expression varied among species, with ovine corneal endothelium showing a relative delay in detectable reporter gene expression compared with the rat or human corneal endothelium. Vectors containing the myeloproliferative sarcoma virus promoter or the phosphoglycerate kinase promoter were not significantly more effective than LV-SV40-eYFP. The stability of eYFP expression in rat and ovine corneas following ex vivo transduction of the donor cornea was assessed following orthotopic corneal transplantation. Following transduction ex vivo, eYFP expression was maintained in corneal endothelial cells for at least 28 days after corneal transplantation in the sheep and 460 days in the rat. Thus, rat, ovine and human corneal endothelial cells were efficiently transduced by the LV, and gene expression appeared stable over weeks in vivo. Gene Therapy (2007) 14, 760-767.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lentivirus-mediated gene transfer to the rat, ovine and human cornea

et al. 2007

View full text Add to dashboard Cite

show abstract

“…This approach is applicable to gene delivery ex vivo, for example, to endothelial cells prior to transplantation of organs such corneas [40][41][42][43] or to autologous transplantation of vessels in procedures such as coronary artery or peripheral vascular bypass grafts [44,45]. It is also a step in the production of totally targeted non-viral vectors.…”

Section: Discussionmentioning

confidence: 99%

Antibody targeted gene transfer to endothelium

Tan

Manunta

Ardjomand

et al. 2002

The Journal of Gene Medicine

106

View full text Add to dashboard Cite

We have shown that our novel vector is capable of in vitro and ex vivo gene delivery to cells and human tissues including cornea, artery and vein. In particular, an Ab against E-selectin was effective at selectively delivering genes to activated endothelial cells expressing the adhesion molecule. Such a strategy will have applications for targeting these tissues prior to transplantation or autologous grafting, and, in the longer term, may allow in vivo targeting of gene therapy to inflammatory sites.

show abstract

“…9,10 Human corneas retrieved for transplantation are stored for days to weeks within eye banks, and are thus readily available for manipulation. The corneal endothelium, the primary target for ex vivo gene transfer to a donor cornea, is an accessible monolayer of somatic cells.…”

Section: Genetic Modification Of Corneal Allograftsmentioning

confidence: 99%

“…9,10 Non-viral vectors, although safe, are generally inefficient. 35 The few exceptions, for example the synthetic peptide-based Gene-modified corneal allografts KA Williams et al vector described by Fabre and co-workers, 36 produce only short-term gene expression, of the order of a few days up to a week, in ocular tissues.…”

Section: Vectors For Gene Therapy Of the Corneal Endotheliummentioning

confidence: 99%

Prospects for genetic modulation of corneal graft survival

Williams

Brereton

Coster

2009

Eye

View full text Add to dashboard Cite

Irreversible immunological rejection is the major cause of clinical corneal graft failure. Ex vivo gene therapy directed at the donor cornea has been shown to prolong orthotopic corneal allograft survival significantly in experimental animal models including the mouse, rat, rabbit, and sheep. Transgenes effective in prolonging corneal graft survival include immunomodulatory cytokines and cytokine receptors, an inhibitor of neovascularisation, a blocker of antigen-presenting cell-T cell co-stimulation, nerve growth factor, a dominant negative regulator of apoptosis, and the enzyme indoleamine 2,3-dioxygenase. Although many viral and non-viral vectors have been shown to transduce the corneal endothelium efficiently, allograft survival has so far been prolonged only following transduction of the donor cornea with adenoviral and lentiviral vectors. The degree of graft prolongation, although promising, is still insufficient for immediate translation to the clinic. Increasing the time that the therapeutic gene is expressed in the eye with an integrative, non-immunogenic viral vector is likely to be one way to achieve long-term graft survival. Simultaneous targeting of multiple pathways of graft rejection with more than one transgene is likely to be another. We suggest that the use of an adeno-associated viral or lentiviral vector combined with multiple transgenes may provide the key to future clinical trials.

show abstract

Gene Delivery to the Corneal Endothelium

Cited by 33 publications

References 40 publications

Lentivirus-mediated gene transfer to the rat, ovine and human cornea

Lentivirus-mediated gene transfer to the rat, ovine and human cornea

Antibody targeted gene transfer to endothelium

Prospects for genetic modulation of corneal graft survival

Contact Info

Product

Resources

About