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Rapid drug discovery for retinal degeneration

We try to speed up eye-drug discovery through using the zebrafish model. It is a highly visual animal. Its visual responses have been used to identify eye-disease mutants. For example, many retinal-degeneration mutants lacks an optokinetic response (OKR).

 
The OKR of a retinal-degeneration mutant (top) and its normal sibling (bottom). These larvae are put inside a rotating drum with black and white stripes (the reflection of the pattern can be seen in the air bubble on the left). Even though both larvae look normal, only the bottom one can track the rotating stripes and move its eyes accordingly.

picHistological analysis of the retinas of these larvae. The cone photoreceptors are labelled in yellow. These photoreceptors are degenerating in the mutant but not in the normal sibling. This affects the vision of the mutant and results in no response to the OKR test. Courtesy of Liyun Zhang, a former postdoctoral fellow in the laboratory.

Since the little zebrafish embryos can absorb chemicals through their skin, they can absorb drugs we put in the water. Then, we can efficiently evaluate the potential therapeutic value of the drugs through measuring the resulting effects of drug treatment on the light sensation and associated histology of the zebrafish. Our major screening platform involves testing zebrafish light sensation in multi-well plate (see below). We have been developing statistical and machine-learning approaches to analyze the screening data (Gao et al., 2014; Liu et al., 2015; Gao et al., 2016; Liu et al., 2017). We are screening compounds including traditional Chinese medicines (TCMs) for better vision. To this end, we are collaborating with a number of prominent centers in Hong Kong and China, and have acquired pure compounds, extracts and herbal formulas that are good for vision and/or have been used to treat Chinese retinal degeneration patients successfully. We have begun to identify interesting compounds that may help retinal-degeneration patients (Zhang et al., 2016).

Zebrafish in 96-well plate
Measuring visual behaviour of 96 zebrafish in a 96-well plate.

We have outlined our vision on screening eye drugs with zebrafish in two recent reviews (Zhang et al., 2012; Ganzen et al., 2017). Together with our other research approach on "elucidating gene network", we can effectively deduce the molecular pathways through which drug candidates exert their therapeutic effects.