Combined Effect of Cyclosporine and Sirolimus on Improving the Longevity of Recombinant Adenovirus–Mediated Transgene Expression in the Retina

Shen, Wei; Lai, May C.; Beilby, John; Barnett, Nigel L.; Liu, Jie; Constable, Ian J.; Rakoczy, P. Elizabeth

doi:10.1001/archopht.119.7.1033

Cited by 19 publications

(10 citation statements)

References 31 publications

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“…Ten-month-old mcd/mcd and C57BL/6 mouse eyes were assessed using electroretinography as previously described, 29 but using flash stimulus at 0.25 Hz and four consecutive responses. Stimulus-response characteristics were generated by attenuating the flash intensity with neutral density filters.…”

Section: Electroretinographymentioning

confidence: 99%

Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model

Rakoczy

Zhang

Robertson

et al. 2002

The American Journal of Pathology

155

115

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Section: Electroretinographymentioning

confidence: 99%

Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model

Rakoczy

Zhang

Robertson

et al. 2002

The American Journal of Pathology

155

115

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“…Ultrapurification of the PS-oligos by strong anion exchange chromatography might produce a safer profile in the future clinical setting (Flores-Aguilar et al, 1997). It is mostly likely that the cellular infiltration is associated with the temporary breakdown of the blood-retina barrier that occurs following transscleralchoroidal-RPE subretinal injection (Reichel et al, 1998;Shen et al, 2001). However, in areas far from the injection site where the fluorescent signal was strongly observed, cellular infiltration was not observed, and the retinal morphology was very well preserved ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The prepared retinal and RPE-choroid-sclera flat mounts were examined by fluorescence microscopy to evaluate the distribution of FL-oligo in the neuroretina and RPE cells. Cryosections of 12-14 mm thickness were produced for detection of cellular uptake and distribution of FLoligo and for immunophenotyping of CD4 1 and CD8 1 cytotoxic T lymphocytes and CD68 macrophages (Shen et al, 1998(Shen et al, , 2001. Mouse antirat CD4 1 (1:50), CD8 1 (1:50), and CD68 (1:500) monoclonal antibodies (mAb) were obtained from Serotec Inc. (Kidlington, Oxford, U.K.).…”

Section: Fluorescence Microscopy and Immunohistochemistrymentioning

confidence: 99%

Uptake Dynamics and Retinal Tolerance of Phosphorothioate Oligonucleotide and Its Direct Delivery into the Site of Choroidal Neovascularization Through Subretinal Administration in the Rat

Shen

Rakoczy²

2001

Antisense and Nucleic Acid Drug Development

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This study aimed to investigate uptake dynamics and retinal tolerance of phosphorothioate oligonucleotides (PS-oligos) following subretinal injection. A fluorescent-labeled PS-oligo (FL-oligo) with random sequence was administered into the subretinal space of rat by transsclera-choroid-retinal pigment epithelium (RPE) injection at doses of 0.129, 1.29, and 12.9 microg in 2.0 microl solution. The uptake dynamics were evaluated by fundus fluorescent photography in real time and by fluorescence microscopy using flat mounts and cryosections. Immunophenotyping for CD4+, CD8+ cytotoxic lymphocytes, and CD68+ macrophages was performed to assess cellular infiltration in the retina. In addition, the FL-oligo was injected subretinally in a rat model of choroidal neovascularization (CNV) for direct delivery into the site of CNV. Subretinal administration of FL-oligo resulted in both dose-dependent and time-dependent distribution in the retina, where it accessed the RPE and all layers of the neuroretina. CD4+, CD8+ cytotoxic lymphocytes, and CD68+ macrophages were observed at the site of needle penetration. However, in areas far from the injection site where the FL-oligo appeared strongly, cellular infiltration was absent, and the retinal morphology was preserved very well. The FL-oligo was successfully delivered into the site of intense laser photocoagulation. It was predominantly localized to the RPE, macrophages, and some choroid cells and remained detectable for at least 56 days after injection. Our results demonstrate for the first time that subretinal injection efficiently introduced PS-oligo into the RPE and neuroretina with an acceptable level of safety. Subretinal administration of antiangiogenic oligonucleotides may hold great potential for the treatment of CNV.

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“…First-generation Ad vectors were strongly immunogenic, with immunosuppressive drugs needed to extend transgene expression [47,48]. However, second-generation Ad vectors have overcome Ad immunogenicity to some extent by introduction of a mutation in the Ad E2a gene [49], or deletion in E4 [50] with only modest success [51].…”

Section: Adenovirusesmentioning

confidence: 99%

Delivery Systems for Gene Transfer

Collins¹

2010

Genomics

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Combined Effect of Cyclosporine and Sirolimus on Improving the Longevity of Recombinant Adenovirus–Mediated Transgene Expression in the Retina

Cited by 19 publications

References 31 publications

Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model

Progressive Age-Related Changes Similar to Age-Related Macular Degeneration in a Transgenic Mouse Model

Uptake Dynamics and Retinal Tolerance of Phosphorothioate Oligonucleotide and Its Direct Delivery into the Site of Choroidal Neovascularization Through Subretinal Administration in the Rat

Delivery Systems for Gene Transfer

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