July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Novel Small Molecule Aldehyde Sequestering Agents Demonstrate Broad Therapeutic Potential for Ocular Inflammation
Author Affiliations & Notes
  • Susan Macdonald
    Aldeyra Therapeutics, Lexington, Massachusetts, United States
  • Adna Halilovic
    Aldeyra Therapeutics, Lexington, Massachusetts, United States
  • Todd Brady
    Aldeyra Therapeutics, Lexington, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Susan Macdonald, Aldeyra Therapeutics (E); Adna Halilovic, Aldeyra Therapeutics (E); Todd Brady, Aldeyra Therapeutics (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 2663. doi:
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    • Get Citation

      Susan Macdonald, Adna Halilovic, Todd Brady; Novel Small Molecule Aldehyde Sequestering Agents Demonstrate Broad Therapeutic Potential for Ocular Inflammation. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2663.

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

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Abstract

Purpose : Pro-inflammatory aldehydes, such as malondialdehyde (MDA), 4-hydroxy-nonenal, glyoxal, methylglyoxal, and retinal, have been implicated in the pathogenesis of several ocular inflammatory diseases. Recently, the aldehyde trap, reproxalap (ADX-102), demonstrated statistically and clinically significant activity in Phase 2 clinical trials in allergic conjunctivitis, dry eye disease, and noninfectious anterior uveitis. To demonstrate the potential of aldehyde trapping in inflammatory diseases involving the anterior and posterior segments of the eye, 2 structurally distinct aldehyde traps were tested in 2 models of ocular inflammation.

Methods : In a knockout model (abcr-/-) of macular degeneration (MD), in which the retinal transport protein, ABCA4 is not expressed, mice were treated intraperitoneally (IP) for 56 days with 10 mg/kg reproxalap, ADX-103, or vehicle. In this model, retinal escapes the light cycle and forms a toxic metabolite with phosphatidylethanolamine: N-retinylidene phosphatidylethanolamine (A2E). In a rat model of lipopolysaccharide (LPS)-induced uveitis, 50 µg of reproxalap or ADX-103 was topically administered to the eye (TO) 5 times over 24 hours, or by 1 intravitreal (IVT) injection (25 µg), after LPS induction. Ocular exams were performed 6 and 24 hours after LPS injection, after which retina-choroid specimens were processed for MDA adduct ELISA.

Results : In the MD model, daily reproxalap or ADX-103 treatment reduced formation of A2E by 71% (p = 0.011) or 69% (p = 0.002), respectively, compared with vehicle controls. In the LPS-induced uveitis model, after TO administration, total ocular exam scores, including assessments of conjunctiva, lens, cornea and retina, were significantly improved in treated groups, compared to control groups, at 6 hours (p = 0.006 and 0.001 for reproxalap and ADX-103, respectively) and 24 hours (p = 0.004 and 0.04 for reproxalap and ADX-103, respectively). After IVT administration of reproxalap or ADX-103, sums of mean retina/choroid scores were significantly improved vs. vehicle (p = 0.0009 and 0.0026, respectively). Small, although not significant, reductions in MDA adducts were observed in the reproxalap and ADX-103 groups.

Conclusions : In aggregate, the data suggest that aldehyde sequestration has potential for broad anti-inflammatory therapy in the eye by multiple routes of administration, and with distinct chemical structures.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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