Evaluation of adenovirus-delivered human CD59 as a potential therapy for AMD in a model of human membrane attack complex formation on murine RPE

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

doi:10.1167/iovs.08-2025

Cited by 38Retinal Diseases and TreatmentsComplement system in diseasesRetinal Development and Disorders

Evaluation of adenovirus-delivered human CD59 as a potential therapy for AMD in a model of human membrane attack complex formation on murine RPE

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Ramo, Kasmir, Cashman, Siobhan M., Kumar-Singh, Rajendra·2008·Investigative Opthalmology & Visual Science

DOI 10.1167/iovs.08-2025PMC PMC4139013

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Abstract

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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Several experiments using mouse models of laser-induced CNV have demonstrated that all complement pathways, particularly the alternative and terminal pathways, play a significant role in angiogenesis.
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From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [157]

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Authors: Ramo, K., Cashman, S. M., & Kumar-Singh, R.
Affiliations: Tufts University (US)
Venue: Investigative Opthalmology & Visual Science
Publisher: Association for Research in Vision and Ophthalmology (ARVO)
Published: 2008-09-01
Volume: 49
Issue: 9
Pages: 4126
ISSN: 0146-0404 (ISSN-L)
1552-5783
DOI: 10.1167/iovs.08-2025
PMC: PMC4139013
OpenAlex: W2022658314
Cited by: 38
References: 46
Citations by year: 2025: 2 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 2 · 2012: 3
FWCI: 3.37
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Investigative Ophthalmology & Visual Science (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Eye Institute (EY014991, R01EY014991, R01EY013837, R01EY021805, EY 013887)
Topics: Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Keywords: age-related macular degeneration, CD59, complement regulation, membrane attack complex, retinal pigment epithelium, adenoviral gene transfer, complement-mediated lysis, humanized mice, cornea, subretinal injection, Bruch's membrane
MeSH terms: Adenoviridae, Adult, Aging, Animals, Cell Line, Embryo, Mammalian, Flow Cytometry, Genetic Vectors, Humans, Macular Degeneration, Mice, Inbred C57BL, Models, Biological, Pigment Epithelium of Eye, Complement Membrane Attack Complex, Cell Culture Techniques, CD59 Antigens, Mice

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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

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