IGF1 Gene Therapy for Agerelated Macular Degeneration

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Slide 1 :

Modulation of the RPE Phenotype by Insulin-like Growth Factor-1 Transgene Expression Edward Chaum, M.D. Ph.D. Plough Foundation Professor of Retinal Diseases Professor of Ophthalmology, Pediatrics, Anatomy and Neurobiology, and Biomedical Engineering University of Tennessee Health Science Center Hamilton Eye Institute

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RPE Cell Functions Digestion of photoreceptor outer segments Production of trophic hormones Healing response to retinal injury Inhibit choroidal neovascularization Site of outer blood retinal barrier Storage and recycling of Vitamin A Light and heat sink

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Atrophic Macular Degeneration

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Modulating the RPE Phenotype Ideal properties Stimulate RPE cell growth Enhance survival of surrounding cells RPE cells Photoreceptors Recruit RPE cells into areas of atrophy Enhance digestion of ROS membranes Inhibit choroidal neovascularization

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Gene therapy directed to the RPE:IGF-1 growth factor Areas of ongoing investigation: Assess phenotypic effects of IGF-1 in vitro Correlate transgene expression with cell phenotype Enhance IGF-1 transgene expression in vitro Engineer modified growth factor genes Regulate transgene expression in vitro & in vivo

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Lipofection in the RPE

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Lipofection in the RPE

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Flow Cytometry: Endosome Uptake and Transgene Expression

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IGF-1 Growth Factor Stimulates DNA synthesis and cell division Known autocrine & paracrine activity in RPE Stimulates neurite growth in neuronal cells Anti-apoptotic effects May inhibit retinal degeneration Chemotactic activity Angiogenic activity

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IGF-1 Transduction Cascade

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GFP-IGF-1 Fusion Gene Expression in cloned RPE

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Epitope-tagged IGF-1 Plasmid Vector

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Transgenic IGF-1 Transcription in RPE Clones IGF-1 Transgene Cellular IGF-1 + Transgene ß- actin

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Transgene transcription

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Transgenic IGF-1 Protein Synthesis in Control RPE Untransfected RPE

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Transgenic IGF-1 Protein Synthesis in an RPE Clone Epitope-tagged IGF-1

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EGFP:IGF-1 Clones, RT-PCR

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IGF-1 Protein Synthesis in RPE Clones

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IGF-1 Fusion Protein Synthesis in Transduced Clones

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Identification of Epitope-tagged IGF-1 protein

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Morphology of IGF-1 Transduced RPE Clones RPE c14 c49 c62

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Fusion Protein Secretion

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Dose-dependent Enhancement of Cell Proliferation in IGF-1-transduced RPE cells * P<0.05 * P<0.05 * P<0.05

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Dose-dependent Modification of Cell Cycle Kinetics in Synchronized RPE

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IGF-1 Dose-dependent Modification of RPE Growth Characteristics IGF-1 transgene is biologically active Induced IGF-1 gene expression can modulate RPE cell proliferation in vitro Induced IGF-1 gene expression can modulate RPE cell cycle kinetics IGF-1 gene therapy may be a method of enhancing RPE and retinal cell survival

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Gene therapy for ocular disease: Current disease applications Retinitis Pigmentosa Glaucoma Rhodopsin Neuroprotection Peripherin/RDS Trabecular meshwork cGMP PDE Ciliary epithelium Retinoblastoma Cornea RPE dystrophies Stromal scarring Atrophic ARMD Immunomodulation Choroidal neovascularization Proliferative vitreoretinopathy Leber’s congenital amaurosis (RPE65)

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