Hereditary Optic Neuropathies: A Systematic Review on the Interplay between Biomaterials and Induced Pluripotent Stem Cells

Abstract

Hereditary optic neuropathies (HONs) such as dominant optic atrophy (DOA) and Leber Hereditary Optic Neuropathy (LHON) are mitochondrial diseases characterized by a degenerative loss of retinal ganglion cells (RGCs) and are a cause of blindness worldwide. To date, there are only limited disease-modifying treatments for these disorders. The discovery of induced pluripotent stem cell (iPSC) technology has opened several promising opportunities in the field of HON research and the search for therapeutic approaches. This systematic review is focused on the two most frequent HONs (LHON and DOA) and on the recent studies related to the application of human iPSC technology in combination with biomaterials technology for their potential use in the development of RGC replacement therapies with the final aim of the improvement or even the restoration of the vision of HON patients. To this purpose, the combination of natural and synthetic biomaterials modified with peptides, neurotrophic factors, and other low- to medium-molecular weight compounds, mimicking the ocular extracellular matrices, with human iPSC or iPSC-derived cell retinal progenitors holds enormous potential to be exploited in the near future for the generation of transplantable RGC populations.

Keywords: DOA; LHON; RGCs; biomaterial; decellularized extracellular matrix; differentiation; hydrogel; iPSCs; optic neuropathies; synthetic polymer; transplantation.

Figure 1

Annual publication trends in the three bibliographic databases consulted. Results for the three general combinations of keywords: (A) “Retinal Ganglion Cell AND Hereditary Optic Neuropathy”, (B) “Retinal Ganglion Cell AND Stem Cell”, and (C) “Retinal Ganglion Cell AND Induced Pluripotent Stem Cell”.

Figure 2

(A) Retinal ganglion cell. (B) Crossed (red) and uncrossed (blue) fibers in the anterior visual pathway. (C) Fundus photograph showing excavated optic nerve heads of a right (RE) and left eye (LE) with temporal pallor in a DOA patient.

Figure 3

Applications of iPSC technology.

Figure 4

Biomaterials for stem cell expansion, differentiation, and transplantation and the in vivo engrafting of stem cells including types and their most relevant features. Biomaterials are ordered from higher to lower physicochemical complexity and higher to lower biocompatibility.