Clinical and Scientific Considerations for Whole Eye Transplantation: An Ophthalmologist's Perspective

Over 40 million patients worldwide are legally blind from either retinal or optic nerve disease. 1 Retinal neurons, from photoreceptors to retinal ganglion cells (RGCs), have an intrinsically poor capacity for selfrepair after damage and no capacity to self-regenerate.Thus, vision restoration in patients with late-stage macular degeneration or glaucoma will likely require strategies to replace damaged cells.Currently, two major approaches are being pursued: (1) cell typespecific replacement and (2) whole eye transplantation (WET).Both strategies are associated with unique advantages and challenges.For the TVST readership, in this opinion piece, we summarize many of the salient barriers clinician-scientists must overcome to enable approaches like WET to transition from a cosmetic procedure to a surgery that provides functional recovery. Targeted Cell Type-Specific TransplantationSimply put, targeted, cell type-specific transplantation aims to replace non-functioning degenerated cells with healthy cells.The success of targeted cellular replacement strategies depends on the ability to generate a large volume of healthy, immune-compatible, high-grade cells that would need to be integrated into the neurosensory retina.Thankfully, advances in stem cell biology have enabled the production of patient-derived RGC-like and photoreceptor-like cells. 2,3Athough these cells display morphologic and electrophysiologic characteristics similar to native cells, critical functional differences still limit clinical translation.Additionally, standardizing good laboratory practices that allow for affordable and reproducible production of cells for transplantation is needed.Even if the barriers mentioned above are addressed, cellular integration is the major challenge limiting the translation of cell-type-specific transplantation.In the case of photoreceptor disease, scientists have successfully transplanted human embryonic stem cell-derived retinal pigment epithelium (RPE) cells by loading them onto ultrathin, bioinert parylene sheets, for transplanting cells subretinally. 4The parylene sheet allows RPE cells to maintain their apical-basal orientation and for cells to be inserted into the correct tissue layer.One year after implantation, many patients reported >5 letter gain in best-corrected visual recovery in the treated eye and >5 letter loss in the untreated eye. 4 Such efforts, however, are even more complicated if photoreceptors or RGCs need replacing. 3Restoring vision with photoreceptors, for example, requires cells to not only physically reside in the correct retinal layer, with the correct apical to basal orientation, but also for their dendritic processes and axons to synapse with native cells in the retina.RGCs have the added barriers of needing approaches that can direct axon regeneration out of the eye, into the optic nerve, to the diencephalon, and drive synaptic formation with intracranial neurons.Complicating matters further is that there is no guarantee that intravitreal delivery of a suspension of RGCs would result in the correct RGC subtype to integrate into the areas where they are "missing."Few, if any, approaches have been described that can deliver this.