June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Dark Adaptation Delays and Retinaldehyde Dimerization Products
Author Affiliations & Notes
  • Leonide Saad
    Harkness Eye Institute, Columbia University Medical Center, New York, New York, United States
    Alkeus Pharmaceuticals, Boston, Massachusetts, United States
  • Dan Zhang
    Harkness Eye Institute, Columbia University Medical Center, New York, New York, United States
  • Ilyas Washington
    Harkness Eye Institute, Columbia University Medical Center, New York, New York, United States
  • Footnotes
    Commercial Relationships   Leonide Saad, Alkeus Pharmaceuticals (E), Alkeus Pharmaceuticals (S); Dan Zhang, None; Ilyas Washington, Alkeus Pharmaceuticals (C), Alkeus Pharmaceuticals (P)
  • Footnotes
    Support  NIH Grant EY021207
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 5407. doi:
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      Leonide Saad, Dan Zhang, Ilyas Washington; Dark Adaptation Delays and Retinaldehyde Dimerization Products. Invest. Ophthalmol. Vis. Sci. 2017;58(8):5407.

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

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Abstract

Purpose : To elucidate the role of retinaldehyde dimerization products (RDP) on age-associated declines of dark adaptation.

Methods : Slowed dark adaptation occurs almost universally during the course of aging. However, the molecular mechanisms responsible for such delays are unknown. RDP are small molecule byproducts of the vitamin A cycle and are implicated in the pathogenesis of several retinal diseases. We used UPLC to quantify the amount of vitamin A and RDP in human eyes. To evaluate the effects of RDP on dark adaptation, we used a mouse model that displays increased ocular RDP, and modulated RDP in the animals by administering C20D3-vitamin A (ALK-001), a vitamin A with reduced dimerization propensity. Ocular RDP was also modulated in a wild-type rodent by intravitreal delivery of RDP. Dark adaptation was assessed by measuring the recovery of electroretinograms and rhodopsin regeneration kinetics following a controlled bleach. We used 2-tailed t-tests for statistical analyses.

Results : RDPs accumulate with age in the human retina while total vitamin A remains stable: at approximately 70 years of age, the amount of RDP can surpass ocular vitamin A (~20,000 pmols per retina, N=18). In mouse models of accelerated RDP formation, ALK-001 retarded the age-related accumulation of RDP by over 80% (N=10, p<0.01) and reduced fundus autofluorescence (FAF) by about 70% (Fig. a).
Mice that received ALK-001 had over 2-fold faster b-wave recovery than mice in the vitamin A group (N=10, p<0.01). Wild-type rodents intraocularly treated with a bolus of RDP soon displayed a 30% slowing of b-wave recovery, despite otherwise normal retinal electrophysiology and morphology. The observed delays in dark adaptation could be explained by RDP-induced delays in rhodopsin regeneration.

Conclusions : The age-related accumulation of RDP is sufficient alone to cause age-related declines in dark adaption. Data further show that progressive declines in dark adaptation are tractable to pharmacological intervention and reveal RDP as a therapeutic target. Finally, ALK-001 holds promise as a non-invasive, early preventive therapeutic to mitigate ubiquitous declines in visual performance.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

FAF (Fig. a) and b-wave amplitude (Fig b.) of mice reared on vitamin A or C20D3-vitamin A.

FAF (Fig. a) and b-wave amplitude (Fig b.) of mice reared on vitamin A or C20D3-vitamin A.

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