Abstract
Retinal neovascularization is central to the pathogenesis of proliferative diabetic retinopathy, the leading cause of blindness among the middle-aged population. Angiostatin, a proteolytic fragment of plasminogen is one of the most promising inhibitors of angiogenesis currently in clinical trials. Here we show that recombinant angiostatin can inhibit retinal neovascularization in a mouse model of proliferative retinopathy. Because proliferative diabetic retinopathy is a recurrent disease, effective therapy will need to be sustained. Recombinant adeno-associated viruses permit long-term expression of transfected genes; however, they can only accommodate a small insert sequence. Thus, we engineered and tested a shortened recombinant angiostatin derivative containing a signal sequence to permit secretion. Recombinant protein was purified from the medium of transfected HEK293 cells and injected subcutaneously into treated animals. The retinal vasculature was analyzed in retinal flat mounts and using immunohistochemically stained sections. Both methods demonstrate that this short, secreted form of angiostatin is effective in reducing the development of blood vessels in a nontumor environment and has therapeutic potential for neovascular retinopathies such as diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion and, possibly, age-related macular degeneration.
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Acknowledgements
We thank Drs Myrna Rosenfeld and Anna Francesconi for discussions and Dr Francis Castellino for providing a plasmid containing human plasminogen cDNA. This research was supported by grants EY09534, EY13101 and AI22251 from the National Institutes of Health.
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Meneses, P., Hajjar, K., Berns, K. et al. Recombinant angiostatin prevents retinal neovascularization in a murine proliferative retinopathy model. Gene Ther 8, 646–648 (2001). https://doi.org/10.1038/sj.gt.3301423
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DOI: https://doi.org/10.1038/sj.gt.3301423