Subretinal transplantation of retinal pigment epithelium overexpressing fibulin-5 inhibits laser-induced choroidal neovascularization in rats

Li, Fuliang; Zeng, Yuxiao; Xu, Haiwei; Yin, Zheng

doi:10.1016/j.exer.2015.05.004

Cited by 14 publications

(10 citation statements)

References 35 publications

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“…Because the use on anti-VEGFs for the treatment of neovascular AMD is effective in only 30%–40% of patients and because it is necessary that anti-VEGFs be injected intraocularly every 4–8 weeks for the life of the patient and because the treatment is costly 9 , 10 and may elicit significant side effects, 11 , 12 , 31 , 32 it is imperative that novel, long-lasting, and more effective treatments be discovered. 18 We have proposed the transplantation of PEDF -transfected pigment epithelial cells as a long-term alternative to the frequent intraocular injections of anti-VEGFs for the treatment for nAMD.…”

Section: Discussionmentioning

confidence: 99%

“…The delivery of anti-angiogenic factors to the retina using gene therapy could be approached by the direct administration 17 or transplantation of ex vivo engineered RPE cells expressing anti-angiogenic factors. 18 In a number of cases, the gene is delivered using adeno-associated virus (AAV) vectors; however, the required re-administration may compromise efficacy 19 and might induce an immune response. Recent clinical studies showed that intravitreal sFLT01 20 and subretinal endostatin/angiostatin 21 injections seemed to be safe and well tolerated, although the efficacy in the CNV reduction was not confirmed.…”

Section: Introductionmentioning

confidence: 99%

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Long-Term PEDF Release in Rat Iris and Retinal Epithelial Cells after Sleeping Beauty Transposon-Mediated Gene Delivery

García-García¹,

Recalde²,

Hernández³

et al. 2017

Molecular Therapy - Nucleic Acids

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Pigment epithelium derived factor (PEDF) is a potent antiangiogenic, neurotrophic, and neuroprotective molecule that is the endogenous inhibitor of vascular endothelial growth factor (VEGF) in the retina. An ex vivo gene therapy approach based on transgenic overexpression of PEDF in the eye is assumed to rebalance the angiogenic-antiangiogenic milieu of the retina, resulting in growth regression of choroidal blood vessels, the hallmark of neovascular age-related macular degeneration. Here, we show that rat pigment epithelial cells can be efficiently transfected with the PEDF-expressing non-viral hyperactive Sleeping Beauty transposon system delivered in a form free of antibiotic resistance marker miniplasmids. The engineered retinal and iris pigment epithelium cells secrete high (141 ± 13 and 222 ± 14 ng) PEDF levels in 72 hr in vitro. In vivo studies showed cell survival and insert expression during at least 4 months. Transplantation of the engineered cells to the subretinal space of a rat model of choroidal neovascularization reduces almost 50% of the development of new vessels.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Long-Term PEDF Release in Rat Iris and Retinal Epithelial Cells after Sleeping Beauty Transposon-Mediated Gene Delivery

García-García¹,

Recalde²,

Hernández³

et al. 2017

Molecular Therapy - Nucleic Acids

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“…Numerous studies have showed encouraging results by transplanting RPE suspensions or RPE sheets into the subretinal space of animal models [4][5][6][7]. However, AMD patients who received RPE transplantation did not achieve significant visual improvements in FDAapproved clinical trials [8,9].…”

Section: Introductionmentioning

confidence: 97%

Effects of low-level laser irradiation on proliferation and functional protein expression in human RPE cells

Dang

et al. 2015

Lasers Med Sci

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Low-level laser irradiation (LLLI) modulates a set of biological effects in many cell types such as fibroblasts, keratinocytes, and stem cells. However, no study to date has reported the effects of LLLI on retinal pigment epithelia (RPE) cells. The aim of this study was to investigate whether LLLI could enhance the proliferation of RPE cells and increase the expression of RPE functional genes/proteins. Human ARPE-19 cells were seeded overnight and treated with 8 J/cm(2) of LLLI. Cell proliferation was measured by CCK8 assay and cell cycle distribution was evaluated by FACS. The transcription of cell cycle-specific genes and RPE functional genes was quantified by RT-PCR. Moreover, the expression of ZO-1 and CRALBP were evaluated by immunostaining. A dose of 8 J/cm(2) of LLLI significantly increased proliferation and promoted cell cycle progression while upregulating the transcription of CDK4 and CCND1 and decreasing the transcription of CDKN2A, CDKN2C, and CDKN1B in human ARPE-19 cells. Additionally, LLLI enhanced the expression of ZO-1 and CRALBP in human ARPE-19 cells. In conclusion, LLLI could enhance the proliferative ability of human ARPE-19 cells by modulating cyclin D1, CDK4, and a group of cyclin-dependent kinase inhibitors. It also could increase the expression of RPE-specific proteins. Thus, LLLI may be a potential approach for the treatment of RPE degenerative diseases.

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“…[65] . In rats, photoreceptor degeneration can be prevented by subretinal transplantation of human fetal lung fibroblasts expressing the ciliary neurotrophic factor gene [66] , and laser-induced choroidal neovascularization can be inhibited by subretinal transplantation of RPE overexpressing fibulin-5 [67] . Of all of the cell types, progenitor cells and stem cells, such as human neural progenitor cells [68] , human retinal progenitor cells [69] , progenitor cells from the porcine neural retina [70] , forebrain progenitor cells [71] , brain-derived precursor cells [72] , human embryonic stem cell-derived retinal progenitors [73] , human RPE stem cells [74] , human bone marrow mesenchymal stem cells [75] , and rat mesenchymal stem cells [76] , are the most popular when given subretinally for cell replacement therapy for retinal degeneration.…”

Section: Gene Therapymentioning

confidence: 99%

Subretinal Injection: A Review on the Novel Route of Therapeutic Delivery for Vitreoretinal Diseases

Peng

Tang

Zhou³

2017

Ophthalmic Res

133

117

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Compared to intravitreal injection, subretinal injection has more direct effects on the targeting cells in the subretinal space, which provides a new therapeutic method for vitreoretinal diseases, especially when gene therapy and/or cell therapy is involved. To date, subretinal delivery has been widely applied by scientists and clinicians as a more precise and efficient route of ocular drug delivery for gene therapies and cell therapies including stem cells in many degenerative vitreoretinal diseases, such as retinitis pigmentosa, age-related macular degeneration, and Leber's congenital amaurosis. However, clinicians should be aware of adverse events and possible complications when performing subretinal delivery. In the present review, the subretinal injection used in vitreoretinal diseases for basic research and clinical trials is summarized and described. Different methods of subretinal delivery, as well as its benefits and challenges, are also briefly introduced.

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Subretinal transplantation of retinal pigment epithelium overexpressing fibulin-5 inhibits laser-induced choroidal neovascularization in rats

Cited by 14 publications

References 35 publications

Long-Term PEDF Release in Rat Iris and Retinal Epithelial Cells after Sleeping Beauty Transposon-Mediated Gene Delivery

Long-Term PEDF Release in Rat Iris and Retinal Epithelial Cells after Sleeping Beauty Transposon-Mediated Gene Delivery

Effects of low-level laser irradiation on proliferation and functional protein expression in human RPE cells

Subretinal Injection: A Review on the Novel Route of Therapeutic Delivery for Vitreoretinal Diseases

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