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AAV-mediated expression of human PRELP inhibits complement activation, choroidal neovascularization and deposition of membrane attack complex in mice

Gene Therapy volume 21, pages 507–513 (2014)Cite this article

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Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Approximately 50% of AMD patients have a polymorphism in the negative regulator of complement known as Factor H. Individuals homozygous for a Y402H polymorphism in Factor H have elevated levels of membrane attack complex (MAC) in their choroid and retinal pigment epithelium relative to individuals homozygous for the wild-type allele. An inability to form MAC due to a polymorphism in C9 is protective against the formation of choroidal neovascularization (CNV) in AMD patients. Hence, blocking MAC in AMD patients may be protective against CNV. Here we investigate the potential of human proline/arginine-rich end leucine-rich repeat protein (PRELP) as an inhibitor of complement-mediated damage when delivered via the subretinal route using an AAV2/8 vector. In a fluorescence-activated cell sorting (FACS) lysis assay, PRELP inhibited normal human serum-mediated lysis of Hepa-1c1c7 cells by 18.7%. Unexpectedly, PRELP enhanced the formation of tubes by human umbilical vein endothelial cells (HUVECs) by approximately 240%, but, when delivered via an AAV vector to the retina of mice, PRELP inhibited laser-induced CNV by 60%. PRELP reduced deposition of MAC in vivo by 25.5%. Our results have implications for the development of complement inhibitors as a therapy for AMD.

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Acknowledgements

This study was supported by grants to RKS from The Ellison Foundation, The Virginia B Smith Trust, The National Institute of Health/NEI (EY021805 and EY013837), The Department of Defense/ TATRC, The Paul and Phyllis Fireman Charitable Foundation and grants to the Department of Ophthalmology at Tufts University School of Medicine from the Lions Eye Foundation and Research to Prevent Blindness.

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  1. Department of Ophthalmology, Tufts University School of Medicine, Boston, MA, USA

    M T Birke, E Lipo, M Adhi, K Birke & R Kumar-Singh

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  1. M T Birke
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Correspondence to R Kumar-Singh.

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Birke, M., Lipo, E., Adhi, M. et al. AAV-mediated expression of human PRELP inhibits complement activation, choroidal neovascularization and deposition of membrane attack complex in mice. Gene Ther 21, 507–513 (2014). https://doi.org/10.1038/gt.2014.24

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