Abstract
Inherited optic neuropathies share visual impairment due to the degeneration of retinal ganglion cells (RGCs) as the hallmark of the disease. This group of genetic disorders are caused by mutations in nuclear genes or in the mitochondrial DNA (mtDNA). An impaired mitochondrial function is the underlying mechanism of these diseases. Currently, optic neuropathies lack an effective treatment, and the implementation of induced pluripotent stem cell (iPSC) technology would entail a huge step forward. The generation of iPSC-derived RGCs would allow faithfully modeling these disorders, and these RGCs would represent an appealing platform for drug screening as well, paving the way for a proper therapy. Here, we review the ongoing two-dimensional (2D) and three-dimensional (3D) approaches based on iPSCs and their applications, taking into account the more innovative technologies, which include tissue engineering or microfluidics.
Highlights
Stem Cell-Based 2D/3D Approaches.Hereditary optic neuropathies are a heterogeneous group of disorders mainly characterized by progressive visual impairment and optic atrophy, with an estimated prevalence of 1 in 10,000 individuals [1]
In the last years, significant progress has been made on retinal ganglion cells (RGCs) generation from induced pluripotent stem cell (iPSC) with both 2D and 3D approaches, thanks to the knowledge of in vivo retina development
There is evidence that these models represent an interesting platform for drug screening, since some molecules have been found to be able to rescue the affected phenotype in patients’ iPSC-derived RGCs
Summary
Hereditary optic neuropathies are a heterogeneous group of disorders mainly characterized by progressive visual impairment and optic atrophy, with an estimated prevalence of 1 in 10,000 individuals [1] These disorders share mitochondrial dysfunction as their primary pathophysiological mechanism, which causes the degeneration of retinal ganglion cells (RGCs) and their axons, leading to optic nerve atrophy [2]. Yu-Wai-Man et al provided both clinical and preliminary experimental evidence for a bilateral effect of unilateral intravitreal injections of a recombinant replication-defective adeno-associated virus targeting RGCs of LHON patients [7]. These findings could have major implications for gene therapy clinical trial design and outcome measures. We recapitulate the foremost applications of iPSC-derived RGCs in the context of hereditary optic neuropathies, comprising two-dimensional (2D) and threedimensional (3D) approaches, and the concrete examples already conducted to date
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