iPSC derived retinal organoids for in vitro safety and efficacy screening
Drug induced ocular toxicity or specifically retinal toxicity is a relatively rare occurrence but with potentially life changing impacts for patients. There is a range of existing drugs with well-known retinal toxicity including anti-malarial, anti-cancer and a selection of other important marketed drugs. In development, if there is evidence that compounds have the potential to cause adverse reactions then pre-clinical assessment is warranted.
Historically, pre-clinical assessment of retinal toxicity has used ex vivo animal retinal explants or single retinal cell types that are poor representations of the complex human retina. The development and validation of iPSC derived retinal organoids by Newcells represents a major advance in in vitro to in vivo extrapolation (IVIVE).
Retinal organoids can also be used to assess the efficacy of therapies targeting retinopathies. There are over 250 genes associated with inherited retinopathies and this class of disease effects 1 in 2,000-3,000 individuals. Using iPSC technology it is possible to produce retinal organoids that contain retinopathy specific mutations enabling the testing of new therapies for efficacy.
Our iPSC derived retinal organoid platform
- Contains all of the major retinal cell types found in vivo, organised into a functional organoid
- Is light responsive, enabling electrophysiological measurement of toxicological and therapeutic impacts on this key functional activity
- Responds to known toxins with responses similar to that seen in vivo
- Rat and non-human primate (NHP) systems are being developed to allow comparison of results from preclinical animal studies with human models and reduce the use of animals
- Can be created with iPSCs from patients with inherited retinal diseases to produce disease models for efficacy and screening studies
Figure I : Immunohistochemistry staining of human retinal organoids showing presence of key cell types
Assessment of retinal toxicity
The organoids are an ideal platform for assessment of retinal toxicity and for the modelling of retinopathies particularly inherited rare diseases such as retinitis pigmentosa, Ushers syndrome and Stargadt disease.
Newcells have developed and are characterising retinal organoids containing microglia that offer an improved model of the retina for safety and disease modelling studies.
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Chichagova V, Hilgen G, Ghareeb A, Georgiou M, Carter M, Sernagor E, Lako M, Armstrong L. Human iPSC differentiation to retinal organoids in response to IGF1 and BMP4 activation is line- and method-dependent. Stem Cells. 2020 Feb;38(2):195-201.
Hallam D, Hilgen G, Dorgau B, Zhu L, Yu M, Bojic S, Hewitt P, Schmitt M, Uteng M, Kustermann S, Steel D, Nicholds M, Thomas R, Treumann A, Porter A, Sernagor E, Armstrong L, Lako M. Human-Induced Pluripotent Stem Cells Generate Light Responsive Retinal Organoids with Variable and Nutrient-Dependent Efficiency. Stem Cells. 2018 Oct;36(10):1535-1551.