May 2005
Volume 46, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2005
AL–39324: A Potential 2nd Generation Agent for the Treatment of Pathologic Choroidal Neovascularization (CNV)
Author Affiliations & Notes
  • D.P. Bingaman
    Retina Discovery Unit, Alcon Research Ltd, Fort Worth, TX
  • C. Liu
    Retina Discovery Unit, Alcon Research Ltd, Fort Worth, TX
  • R.A. Landers
    Retina Discovery Unit, Alcon Research Ltd, Fort Worth, TX
  • X. Gu
    Retina Discovery Unit, Alcon Research Ltd, Fort Worth, TX
  • Footnotes
    Commercial Relationships  D.P. Bingaman, Alcon Research, Ltd. E; C. Liu, Alcon Research, Ltd. E; R.A. Landers, Alcon Research, Ltd. E; X. Gu, Alcon Research, Ltd. E.
  • Footnotes
    Support  None.
Investigative Ophthalmology & Visual Science May 2005, Vol.46, 464. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      D.P. Bingaman, C. Liu, R.A. Landers, X. Gu; AL–39324: A Potential 2nd Generation Agent for the Treatment of Pathologic Choroidal Neovascularization (CNV) . Invest. Ophthalmol. Vis. Sci. 2005;46(13):464.

      Download citation file:


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

      ×
  • Supplements
Abstract

Abstract: : Purpose: Currently, a variety of clinical trials in both ophthalmology and oncology target VEGF signal transduction to achieve inhibition of angiogenesis. Receptor tyrosine kinases (RTKs), e.g., VEGFR–2, mediate pathologic angiogenesis, retinal vascular permeability, and ischemia–related pathophysiology in the eye. The antiangiogenic efficacy of a potent RTK inhibitor, AL–39324 (KDRi IC50=4nM), was investigated in a commonly used mouse model of laser–induced choroidal neovascularization (CNV). Methods: CNV was induced in C57BL/J mice by laser rupture of Bruch’s membrane. Each mouse received 3 laser burns per eye. Local delivery: control mice received laser photocoagulation in both eyes, where one eye received a sham intravitreal (ivt) injection. In drug–treated groups, one eye received a 5ul intravitreal injection of 0%, 0.3%, 1%, or 3% AL–39324 at Day 0 post–laser (prevention paradigm), or a 5µl intravitreal injection of 0%, 1% or 3% AL–39324 or 2µl 1% AL–39324 at Day 7 post–laser (regression paradigm). Also at Day 7 post–laser, several mice with noninjected eyes were euthanized for controls. Systemic administration: mice were randomly assigned as non–treated controls or to oral gavage groups receiving 0, 3, 10, and 20mg/kg/day AL–39324. At Day 14 post–laser in both studies, all mice were euthanized and systemically perfused with fluorescein–labeled dextran. Median and mean CNV areas per mouse were determined via computerized digital analysis of choroidal flat mounts, where P<0.05 was considered significant. Results: Eyes receiving a single ivt injection of 1% AL–39234 and 3% AL–39234 at Day 0 post–laser showed significant prevention of CNV as compared to vehicle–injected eyes (↓84.1%, P=0.004; ↓ 83.0%, P=0.017, respectively). Eyes receiving a single ivt injection of 2µl 1% AL–39324, 5µl 1% AL–39324, and 5µl 3% AL–39324 exhibited regression of existing CNV, when compared to non–treated controls (↓45.4%, P=0.025; ↓41.0%, P=0.039; and ↓29.7%, P=0.012, respectively). Mice treated with 20mg/kg/day AL–39324 showed complete inhibition of CNV (P<0.05). Conclusions: Local and systemic delivery of the RTKi, AL–39324, provides significant, dose–dependent inhibition of laser–induced CNV (80–100%) in the adult mouse. Moreover, AL–39324 was able to induce regression of existing CNV following local delivery. Previous results from this laboratory demonstrated that a single ivt injection of 10% anecortave acetate provided 58% inhibition of CNV. Therefore, AL–39324 may have utility as a 2nd generation agent for the treatment of pathologic choroidal neovascularization in exudative AMD.

Keywords: choroid: neovascularization • receptors: pharmacology/physiology • age-related macular degeneration 
×
×

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.

×