May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Palomid 529, a Non-Steroidal Small Molecule Anti-Angiogenic Agent Inhibits Retinal and Subretinal Neovascularization by Inhibiting the Akt/mtor Pathway
Author Affiliations & Notes
  • D. Sherris
    Paloma Pharmaceuticals Inc, Jamaica Plain, Massachusetts
  • N. S. Bora
    University of Arkansas for Medical Sciences, Little Rock, Arkansas
  • P. S. Bora
    University of Arkansas for Medical Sciences, Little Rock, Arkansas
  • P. McGuire
    University of New Mexico, Albuquerque, New Mexico
  • A. Das
    University of New Mexico, Albuquerque, New Mexico
  • C. Perruzzi
    Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • J. Varnau
    Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • L. Benjamin
    Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • Footnotes
    Commercial Relationships  D. Sherris, Paloma Pharmaceuticals, E; N.S. Bora, None; P.S. Bora, None; P. McGuire, None; A. Das, None; C. Perruzzi, None; J. Varnau, None; L. Benjamin, None.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 3766. doi:https://doi.org/
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      D. Sherris, N. S. Bora, P. S. Bora, P. McGuire, A. Das, C. Perruzzi, J. Varnau, L. Benjamin; Palomid 529, a Non-Steroidal Small Molecule Anti-Angiogenic Agent Inhibits Retinal and Subretinal Neovascularization by Inhibiting the Akt/mtor Pathway. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3766. doi: https://doi.org/.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose: : Characterize small molecule drug inhibitor of anti-angiogenesis in a variety of in vitro models and in vivo models of retinal and subretinal neovascularization.

Methods: : in vitro endothelial cell assays including pro-angiogenic cytokine stimulation, apoptosis, signal transduction mediator responses and matrix metalloproteinase activity. in vivo murine laser-induced neovascularization and murine retinopathy of prematurity models, rabbit retinal detachment models and Evans blue permeability model.

Results: : Retinal diseases of neovasculature create aberrant vessels which induce ocular pathologies initiated by a host of pro-angiogenic factors. Palomid 529, the lead analog for the clinic, broadly inhibits angiogenic cytokine signalling as it inhibits two very different signalling pathways of both VEGF and bFGF induced endothelial cell proliferation with IC50s of 0.02 and 0.2 µM respectively. Palomid 529 further stimulates endothelial cell apoptosis and inhibits matrix metalloproteinase activity, inhibits both endogenous and VEGF induced Akt phosphorylation in endothelial cells showing it as an inhibitor of the PI3/Akt/mTor pathway. Palomid 529 also inhibits VEGF induced angiogenesis in vivo as well as VEGF induced vascular permeability through the Evans blue dye assay. In a both a murine laser-induced retinopathy model and a murine retinopathy of prematurity (ROP) model, Palomid 529 was able to inhibit neovascularization by 65%. Particularly interesting, Palomid 529 was not only able to inhibit aberrant angiogenesis in the ROP model but allow normal angiogenesis to occur. Palomid 529 has extended benefit in a subretinal neovascularization model for at least 28 days after intravitreal administration. Palomid 529 was examined in a rabbit model of retinal detachment which showed a reduction of the presence of glial cells at the site of detachment and elimination of retinal scar formation.

Conclusions: : Results described here show that Palomid 529 inhibits both in vitro and in vivo models of angiogenesis through inhibition of the Akt/mTor signal transduction pathway.

Keywords: age-related macular degeneration • diabetic retinopathy • signal transduction 
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×