PUBLICATION
A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy
- Authors
- Sulaiman, R.S., Merrigan, S., Quigley, J., Qi, X., Lee, B., Boulton, M.E., Kennedy, B., Seo, S.Y., Corson, T.W.
- ID
- ZDB-PUB-160506-2
- Date
- 2016
- Source
- Scientific Reports 6: 25509 (Journal)
- Registered Authors
- Kennedy, Breandan N.
- Keywords
- Angiogenesis, Experimental models of disease, Macular degeneration, Pharmacodynamics, Retinal diseases
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Antibodies, Neutralizing/pharmacology*
- Biological Assay
- Choroid/blood supply
- Choroid/drug effects*
- Choroid/pathology
- Choroidal Neovascularization/genetics
- Choroidal Neovascularization/pathology
- Choroidal Neovascularization/prevention & control*
- Chromones/pharmacology*
- Disease Models, Animal
- Drug Combinations
- Drug Synergism
- Female
- Gene Expression
- Humans
- Intravitreal Injections
- Larva/drug effects
- Mice
- Mice, Inbred C57BL
- Phenylalanine/analogs & derivatives*
- Phenylalanine/pharmacology
- Retina/drug effects
- Retina/pathology
- Tissue Culture Techniques
- Vascular Endothelial Growth Factor A/antagonists & inhibitors*
- Vascular Endothelial Growth Factor A/genetics
- Vascular Endothelial Growth Factor A/metabolism
- Zebrafish
- PubMed
- 27148944 Full text @ Sci. Rep.
Citation
Sulaiman, R.S., Merrigan, S., Quigley, J., Qi, X., Lee, B., Boulton, M.E., Kennedy, B., Seo, S.Y., Corson, T.W. (2016) A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy. Scientific Reports. 6:25509.
Abstract
Ocular neovascularisation underlies blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. These diseases cause irreversible vision loss, and provide a significant health and economic burden. Biologics targeting vascular endothelial growth factor (VEGF) are the major approach for treatment. However, up to 30% of patients are non-responsive to these drugs and they are associated with ocular and systemic side effects. Therefore, there is a need for small molecule ocular angiogenesis inhibitors to complement existing therapies. We examined the safety and therapeutic potential of SH-11037, a synthetic derivative of the antiangiogenic homoisoflavonoid cremastranone, in models of ocular neovascularisation. SH-11037 dose-dependently suppressed angiogenesis in the choroidal sprouting assay ex vivo and inhibited ocular developmental angiogenesis in zebrafish larvae. Additionally, intravitreal SH-11037 (1 μM) significantly reduced choroidal neovascularisation (CNV) lesion volume in the laser-induced CNV mouse model, comparable to an anti-VEGF antibody. Moreover, SH-11037 synergised with anti-VEGF treatments in vitro and in vivo. Up to 100 μM SH-11037 was not associated with signs of ocular toxicity and did not interfere with retinal function or pre-existing retinal vasculature. SH-11037 is thus a safe and effective treatment for murine ocular neovascularisation, worthy of further mechanistic and pharmacokinetic evaluation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping