June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
In vitro lens culture is a potent research tool for assessing chemical toxicity
Author Affiliations & Notes
  • Peter F Kador
    Pharmaceutical Sci, Coll of Pharm, Univ of Nebraska Medical Ctr, Omaha, NE
    Therapeutic Vision, Inc., Omaha, NE
  • Marjorie F Lou
    School of Veterinary Medicine and Biomedical Sciences, University of Nebraska Lincoln, Lincoln, NE
  • Footnotes
    Commercial Relationships Peter Kador, Therapeutic Vision, Inc. (F), Therapeutic Vision, Inc. (S); Marjorie Lou, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2657. doi:
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      Peter F Kador, Marjorie F Lou; In vitro lens culture is a potent research tool for assessing chemical toxicity. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2657.

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

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Abstract

Purpose: The lens can serve as a sensitive indicator of chemical toxicity because it is the largest organ in the body that lacks a vasculature and behaves both electrically and chemically like a single cell. The appearance of lens opacities during the toxicological phase of systemic drug development in long-term rat or dog studies or in preclinical or clinical human studies can quickly result in the death of a promising drug project. Here we demonstrate that the specific adverse biochemical mechanism(s) of action of a candidate drug can quickly be identified by in vitro lens culture studies so that the project may be saved.

Methods: Intact lenses, dissected using a posterior approach, were cultured in vitro using TC-199 - bicarbonate medium containing 30 mM fructose. Basic biochemical analyses included the evaluation of choline, aminoisobutyric acid (AIB), and rubidium uptake, as well as GSH and ATP levels and the activities of GR, GPx, G3PD, G6PDH, LDH, Catalase, and ER stress

Results: While lenses from mouse, rat, rabbit, dog or humans can be successfully cultured in vitro using TC-199 - bicarbonate medium containing 30 mM fructose, intact lens culture studies are distinct from cell culture techniques using standard tissue culture media. Lenticular changes leading to cataract formation were identified within 3 days of culture while the lenses still appeared clear. As a result, culture studies not only can elucidate the experimental mechanism(s) of cataract formation but also identify the toxicological mechanism(s) of action of how a drug can alter lens biochemistry and clarity.

Conclusions: Lens culture studies are a powerful research tool that can rapidly identify the specific adverse mechanism(s) of action of a drug candidate as well as determine whether the parent compound or its metabolite initiates the adverse effect(s).

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