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Originally published In Press as doi:10.1167/iovs.08-2025 on May 16, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:4126-4136.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.08-2025
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Evaluation of Adenovirus-Delivered Human CD59 as a Potential Therapy for AMD in a Model of Human Membrane Attack Complex Formation on Murine RPE

Kasmir Ramo, Siobhan M. Cashman, and Rajendra Kumar-Singh

From the Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts.

PURPOSE. Complement-mediated damage to the retinal pigment epithelium (RPE), Bruch membrane, and choroid has been associated with pathogenesis in age-related macular degeneration (AMD). The terminal step of complement activation involves lysis of cells by the insertion of the membrane attack complex (MAC) in the plasma membrane. The hypothesis that local overexpression of human CD59 (hCD59) delivered by an adenovirus (Ad) vector to primary murine RPE cells in vitro, RPE in vivo, or cornea ex vivo protects those cells from human MAC deposition and lysis was tested.

METHODS. A humanized model of MAC deposition on murine cells and murine ocular tissues including RPE and cornea was developed to permit testing of human complement regulators in mice. A recombinant adenovirus-expressing hCD59 was generated, and this virus was injected into the subretinal space of adult mice. Subsequently, eyecups from these mice were exposed to human serum, and the levels of MAC deposition on the RPE were quantified. hCD59 was also expressed on murine cornea ex vivo and in murine hepatocytes, and primary RPE cells in vitro and levels of human MAC deposition and cell lysis were measured.

RESULTS. Adenovirus-mediated delivery of hCD59 to the RPE, cornea, or cells in culture protects those cells from human MAC deposition and MAC-mediated damage and vesiculation.

CONCLUSIONS. The humanized model of MAC deposition on murine ocular tissues allows testing of human complement regulators that may have potential in the treatment of AMD or other diseases associated with complement activation.




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P. Yang, J. Tyrrell, I. Han, and G. J. Jaffe
Expression and Modulation of RPE Cell Membrane Complement Regulatory Proteins
Invest. Ophthalmol. Vis. Sci., July 1, 2009; 50(7): 3473 - 3481.
[Abstract] [Full Text] [PDF]


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