Customized In Vivo Ocular Models ace

Customized Zebrafish Models of Choroideremia

Zebrafish provide the opportunity to model genetic photoreceptor diseases in the retina and are invaluable in screening candidate disease genes, studying disease pathology, and combating photoreceptor degeneration. Ace Therapeutics is an expert in zebrafish ocular disease models. Our ophthalmic pharmacology experts have successfully generated various models, such as the choroideremia zebrafish model, which helps our customers develop choroideremia therapy for RPE.

Zebrafish Models of Choroideremia

What Is Choroideremia?

Choroidemia (CHM) is an X-linked hereditary retinal degeneration caused by mutations in Rab escort protein 1 (REP1). It has an estimated incidence of 1 in 50,000. CHM is characterized by loss-of-function of REP1 leading to defective prenylation of a subset of Rab proteins, followed by disruption of intracellular trafficking, leading to progressive degeneration of the choroid, RPE, and photoreceptors. The CHM gene is identified as REP1 with disease caused by loss-of-function mutations leading to a truncated, nonfunctional, or rapidly degraded protein. Unlike mammals, the zebrafish choroideremia model relies on a single REP gene. Maternal wild-type REP controls CHM embryo development. Once REP activity declines, so does Rab function, leading to widespread cell death. These features suggest that RPE-correcting therapies can rescue photoreceptor loss in choroideremia. Therefore, zebrafish choroideremia models promise to be an effective tool for evaluating therapies that improve REP1 activity.

Fig. 1. Gross morphology and retinal histology of wild-type (wt), ome and chm mutants at 6 d.p.f. Left panel: coronal retinal sections. (Richardson R, et al., 2017)

Service Overview

Choroidemia (CHM) is a progressive chorioretinal dystrophy caused by mutations in the CHM gene encoding REP1. Ace Therapeutics' researchers have developed a CHM gene mutant zebrafish model. Its features are similar to the degeneration of the RPE and photoreceptors observed in human CHM cases, including initial peripheral RPE hypertrophy and atrophy, followed by progressive cell death in the RPE and peripheral retina, and ultimately severe loss of retinal layers and overall degeneration.

To understand the processes underlying CHM in zebrafish and assess its usefulness as a model of human disease, our researchers characterize patterns of retinal degeneration and correlate them to human pathology through the following strategy.

Histological and morphological studies.
TUNEL test.
Bioinformatics.
Western blot analysis.
Subcellular isolation and in vitro prenylation analysis.

Explore Ace Therapeutics' Zebrafish Models of Choroideremia

Ace Therapeutics presents CHM-mutated zebrafish models of choroideremia generated by random N-ethyl-N-nitrosourea (ENU) mutagenesis, identified in screens for balance and hearing deficits.

It is well known that a key question in the potential treatment of choroideremia is whether photoreceptor degeneration is caused by autonomous defects in opsin trafficking within photoreceptors or whether it is an involuntary and secondary consequence of RPE degeneration. Interestingly, the zebrafish CHM mutant model we provide has only one rep isoform and thus lacks any compensatory function. This provides our customers with a useful tool to characterize therapies aimed at increasing REP1 activity, such as promoting nonsense mutation read-through for novel drug classes.

Ace Therapeutics aims to provide a powerful analytical tool to help our global customers study the mechanism of molecular pathology and potential therapeutic strategies associated with choroidemia. If you are interested in our services or need more detailed information, please feel free to contact us. Our experienced scientists are ready to help you!

References

Richardson R, Tracey-White D, Webster A, et al. The zebrafish eye-a paradigm for investigating human ocular genetics. Eye (Lond). 2017, 31(1):68-86.
Krock BL, Bilotta J, Perkins BD. Noncell-autonomous photoreceptor degeneration in a zebrafish model of choroideremia. Proc Natl Acad Sci U S A. 2007, 104(11):4600-5.

For Research Use Only.

Get in Touch