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Assessment of Vascular Regeneration in the CNS Using the Mouse Retina
Published on: June 23, 2014
Recombinant angiostatin prevents retinal neovascularization in a murine proliferative retinopathy model
P I Meneses1, K A Hajjar, K I Berns
1Department of Microbiology, Weill Medical College of Cornell University, New York, NY, USA.
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.
Insights
A novel short, secreted angiostatin derivative effectively inhibits retinal neovascularization in a mouse model. This offers potential for sustained therapy in diabetic retinopathy and other neovascular eye diseases.
Area of Science:
- Ophthalmology
- Molecular Biology
- Biochemistry
Background:
- Proliferative diabetic retinopathy causes blindness via retinal neovascularization.
- Angiostatin, a plasminogen fragment, inhibits angiogenesis and is in clinical trials.
- Sustained therapy is crucial for recurrent conditions like diabetic retinopathy.
Purpose of the Study:
- To engineer and test a short, secreted recombinant angiostatin for sustained therapeutic effect.
- To evaluate the efficacy of this angiostatin derivative in a mouse model of retinopathy.
- To assess its potential for treating various neovascular retinopathies.
Main Methods:
- Engineered a shortened recombinant angiostatin derivative with a signal sequence for secretion.
- Purified the recombinant protein from transfected HEK293 cells.
- Administered the protein subcutaneously and analyzed retinal vasculature using flat mounts and immunohistochemistry.
Main Results:
- The engineered short, secreted angiostatin effectively inhibited retinal neovascularization in the mouse model.
- Analysis of retinal flat mounts and stained sections confirmed reduced blood vessel development.
- The therapy demonstrated efficacy in a non-tumor environment.
Conclusions:
- The short, secreted angiostatin derivative shows therapeutic potential for neovascular retinopathies.
- This approach could offer sustained treatment for conditions including diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, and age-related macular degeneration.
