Biomedical Engineering Reference
In-Depth Information
Chapter
15
Assessment of Effects on Visual
Function in Larval Zebrafish
Wendy Alderton
CB1 Bio Ltd, Cambridge, UK
15.1 INTRODUCTION
Numerous marketed drugs cause adverse ocular events by affecting the function of the
retina or visual pathways or by causing overt retinal toxicity. Medications that have
been reported to cause adverse ocular effects in the clinic include bisphosphonates;
antiepileptic drugs such as topiramate and vigabatrin; antituberculosis treatments
such as ethambutol and isoniazid; isotretinoin and other retinoids; and amiodarone
(Santaella and Fraunfelder, 2007). The relatively small mass of the eye and its rich
blood supply make it susceptible to adverse effects on visual function for drugs that
cross the blood-retinal barrier.While effects on the eye are reversible if detected early,
if undetected, toxic effects may progress to serious and irreversible ocular damage
(Chiou, 1999). With a few exceptions, the mechanisms of retinal toxicity are poorly
understood. The incidence and impact of retinal toxicity in a typical pharmaceutical
development portfolio has been reported as 6.8% of the failures between 1993 and
2006 were due to retinal toxicity. Although this is a small but measurable incidence,
ocular toxicity does not lend itself to “risk management,” so the impact on a candidate
drug project is potentially serious. Currently, ocular safety is assessed at a late stage in
the preclinical development of a compound. Conventional studies, such as the
measurement of the electroretinogram (ERG) in dogs or rodents, are technically
difficult, labor intensive, and often poorly predictive. Consequently, the lack of a
predictive, convenient method of assessing visual function preclinically has been
recognized by the industry.
The organization of the genome and the genetic pathways controlling signal
transduction and development are highly conserved between zebrafish and man. The
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