A Non Membrane-Targeted Human Soluble CD59 Attenuates Choroidal Neovascularization in a Model of Age Related Macular Degeneration
Open accessAbstract
Age related macular degeneration (AMD) is the most common cause of blindness amongst the elderly. Approximately 10% of AMD patients suffer from an advanced form of AMD characterized by choroidal neovascularization (CNV). Recent evidence implicates a significant role for complement in the pathogenesis of AMD. Activation of complement terminates in the incorporation of the membrane attack complex (MAC) in biological membranes and subsequent cell lysis. Elevated levels of MAC have been documented on choroidal blood vessels and retinal pigment epithelium (RPE) of AMD patients. CD59 is a naturally occurring membrane bound inhibitor of MAC formation. Previously we have shown that membrane bound human CD59 delivered to the RPE cells of mice via an adenovirus vector can protect those cells from human complement mediated lysis ex vivo. However, application of those observations to choroidal blood vessels are limited because protection from MAC- mediated lysis was restricted only to the cells originally transduced by the vector. Here we demonstrate that subretinal delivery of an adenovirus vector expressing a transgene for a soluble non-membrane binding form of human CD59 can attenuate the formation of laser-induced choroidal neovascularization and murine MAC formation in mice even when the region of vector delivery is distal to the site of laser induced CNV. Furthermore, this same recombinant transgene delivered to the intravitreal space of mice by an adeno-associated virus vector (AAV) can also attenuate laser-induced CNV. To our knowledge, this is the first demonstration of a non-membrane targeting CD59 having biological potency in any animal model of disease in vivo. We propose that the above approaches warrant further exploration as potential approaches for alleviating complement mediated damage to ocular tissues in AMD.
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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.
“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 [150,152,153,154,155,156,157,158,159,160,161,162,163].”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [150]
In mice, JNJ-1887 has been shown to reduce laser-induced CNV formation beyond the site of vector delivery, indicating the potential superior coverage of intravitreal versus subretinal gene therapies.
“In mice, JNJ-1887 has been shown to reduce laser-induced CNV formation beyond the site of vector delivery [150], indicating the potential superior coverage of intravitreal versus subretinal gene therapies.”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [150]
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- Authors
- Cashman, S. M., Ramo, K., & Kumar-Singh, R.
- Affiliations
- Tufts University (US)
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-04-28
- Volume
- 6
- Issue
- 4
- Pages
- e19078
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3084256
- OpenAlex
- W2095317976
- Cited by
- 118
- References
- 42
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 8 · 2023: 9 · 2022: 6 · 2021: 17 · 2020: 9 · 2019: 6 · 2018: 4 · 2017: 10 · 2016: 7 · 2015: 5 · 2014: 12 · 2013: 9 · 2012: 7
- FWCI
- 9.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Research to Prevent Blindness
- Ögonfonden
- National Institutes of Health
- National Eye Institute (EY014991, R01EY014991, 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, choroidal neovascularization, CD59, complement system, membrane attack complex, retinal pigment epithelium, adenoviral vector, adeno-associated virus vectors, subretinal gene delivery, intravitreal gene delivery, laser-induced choroidal neovascularization, complement-mediated lysis
- MeSH terms
- Dependovirus, Adenoviridae, Animals, Cell Line, Disease Models, Animal, Humans, Lasers, Macular Degeneration, Retina, Solubility, Genetic Therapy, Complement Membrane Attack Complex, CD59 Antigens, Choroidal Neovascularization, Mice
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