Stargardt Disease Pathology
Stargardt disease is an autosomal recessive disease caused by mutations in the ABCA4 gene. ABCA4 are transporters that clear all-trans-retinal from the photoreceptors. Since the transporters are missing or dysfunctional, there is a build-up of toxic bisretinoid-lipofuscin complex. Accumulation of lipofuscin at larger levels in the photoreceptors leads to the death of photoreceptor cells at the macula and surrounding areas. Due to these events, the pathophysiology in Stargardt disease may present itself as lack of central vision, caused by the degeneration of photoreceptors in the macula i.e. blurred central segment of any visual perceptions; poor night vision due to death of rod cells; and or inability to discriminate colours – achromatopsia, which is death of cone photoreceptors that are responsible for high acuity day light vision.
Homology between Human Eye & Zebrafish Eye
Zebrafish has striking similarities to the human eye in terms of anatomical regions, functions, and the subdivision of photoreceptors.
Signal transduction process from the eye such as retinal phototransduction, light dependent cascade events, movement of ions, conduction of visual messages through optic nerve and the thalamus relay to the cortex region of brain.
Similar physiological activity wherein zebrafish are diurnal. This means that fish have peak activity during high intensity day light and spend more time in an inactive state at night as sleep bouts.
Zebrafish employ visual perception to view predators, moving objects, and the fish can distinguish colour reacting to varying colours.
Zebrafish Model Design for Therapeutic Strategies
ABCA4-/- mutants are created by the CRISPR Cas9 method and genotype, phenotype screening is performed. This screening selection is to ensure that the model zebrafish larvae presents all pathological outcomes observed in human conditions of Stargardt Disease.
Assays for Stargardt Disease
Below are 8 efficacy screening assays performed at Pentagrit for Stargardt Disease:
Latency to Response to Varying Light Intensity in seconds
Visual Acuity Test - Latency to Response to Moving Objects in seconds
Basal linear deposits
% Photoreceptor Degeneration
Retinal Pigment layer Degeneration
Bruch's membrane Thinning
Relative Expression of Inflammatory Markers
Vascular Leakage Score with Neovascularization in Macula
Stargardt Disease - Endpoint Readouts
