Retinal ganglion cell repopulation for vision restoration in optic neuropathy: a roadmap from the RReSTORe Consortium

Abstract

Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system’s limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium’s efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.

Manipulating Myc for reparative regeneration

“…Unlike zebrafish, that can restore vision via the dedifferentiation and proliferation of Müller glia cells that generate all cell types required to regenerate, mammals lose the ability to regenerate their RGCs shortly after birth. Upon injury of the optic nerve, apoptosis of RGCs leads to an irreversible loss of vision ( Boia et al, 2020 ; Soucy et al, 2023 ). Interestingly, single-cell RNA sequencing has shown that Myc is expressed in certain RGC subtypes ( Rheaume et al, 2018 ) and that the expression of Myc mRNA is decreased in the optic nerve by 70%, following injury ( Belin et al, 2015 ).…”

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

“…On the other side, collagen mimetic peptides play a role in the protection of RGCs by restoring collagen fibrillar organization in the ECM [93] peptides obtained from the neural retina and the retinal pigment epithelium (RPE) certainly helps in the maturation of photoreceptors, axon connectivity in the synapsis, and response to light when working with organoids derived from stem cells [85]. Recently, and considering RGCs in particular, a roadmap has been set by the RReSTORe Consortium [94], showing that advances in five key areas are needed to restore the visual pathway damaged by diverse optic neuropathies. These five areas are as follows: (1) RGC development and differentiation, (2) transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) inner retinal wiring, and (5) eye-to-brain connectivity.…”

The Healthy and Diseased Retina Seen through Neuron–Glia Interactions

“…However, many challenges are still ahead, as emphasized by alliances between investigators who are working in collaborative networks to promote advances in this field [485]. Even though the relevant data have been accumulated, it is essential to guarantee that translational approaches are designed to promote the generation and integration of new neurons in the retinal tissue to yield the restoration of lost functions.…”