header logo image header logo text
Downloads Login
Research
General Information
ZIRC
ZFIN ID: ZDB-PUB-160506-2
A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy
Sulaiman, R.S., Merrigan, S., Quigley, J., Qi, X., Lee, B., Boulton, M.E., Kennedy, B., Seo, S.Y., Corson, T.W.
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.
FIGURES
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.
ADDITIONAL INFORMATION