Application of patient-derived induced pluripotent stem cells and organoids in inherited retinal diseases

Abstract

Inherited retinal diseases (IRDs) can induce severe sight-threatening retinal degeneration and impose a considerable economic burden on patients and society, making efforts to cure blindness imperative. Transgenic animals mimicking human genetic diseases have long been used as a primary research tool to decipher the underlying pathogenesis, but there are still some obvious limitations. As an alternative strategy, patient-derived induced pluripotent stem cells (iPSCs), particularly three-dimensional (3D) organoid technology, are considered a promising platform for modeling different forms of IRDs, including retinitis pigmentosa, Leber congenital amaurosis, X-linked recessive retinoschisis, Batten disease, achromatopsia, and best vitelliform macular dystrophy. Here, this paper focuses on the status of patient-derived iPSCs and organoids in IRDs in recent years concerning disease modeling and therapeutic exploration, along with potential challenges for translating laboratory research to clinical application. Finally, the importance of human iPSCs and organoids in combination with emerging technologies such as multi-omics integration analysis, 3D bioprinting, or microfluidic chip platform are highlighted. Patient-derived retinal organoids may be a preferred choice for more accurately uncovering the mechanisms of human retinal diseases and will contribute to clinical practice.

Patient-derived induced pluripotent stem cells with a MERTK mutation exhibit cell junction abnormalities and aberrant cellular differentiation potential

“…Biologically, patient-specific iPSCs are derived from the patient’s own cells, thereby avoiding ethical controversies and legal constraints[ 5 ]. However, for patients with specific gene mutations, iPSCs derived from somatic cell reprogramming usually carry the same gene mutations[ 6 ]. Although these iPSCs or ESCs with mutations may appear to be similar to healthy controls, with unlimited proliferative potential, they may differ in various aspects, such as cell apoptosis, metabolism, proliferation, and directed differentiation potential, compared to healthy PSCs[ 7 , 8 ].…”

Clinical exome analysis and targeted gene repair of the c.1354dupT variant in iPSC lines from patients with PROM1-related retinopathies exhibiting diverse phenotypes

“…iPSC are obtained by reprogramming somatic cells through the introduction of a set of pluripotency transcription factors, originally: Oct3/4, Sox2, c-Myc, and Klf4 [ 38 ]. They provide an accessible and abundant source of cells potentially capable of differentiating into retinal cells such as RPE and photoreceptors, without the ethical concerns associated to Embryonic Stem Cells (ESC) [ 39 ]. Patient-derived iPSC are valuable tools for in vitro disease modelling (disease-in-a-dish) and drug screening for retinal diseases [ 40 ].…”

The application of retinal organoids in ophthalmic regenerative medicine: A mini-review

“…Compared with traditional two-dimensional cell culture system, three-dimensional retinal organoids better simulate the interactions between the microenvironment in each layer in vivo , and provide a new treatment approach for retinal regeneration diseases [ 3 , 4 ]. In this review, we summarize recent development of retinal organoids and discuss their advantages and deficiencies, and highlight their potential applications in ophthalmic regenerative medicine.…”