Advances in repairing the degenerate retina by rod photoreceptor transplantation

Abstract

Despite very different aetiologies, age-related macular degeneration (AMD) and most inherited retinal disorders culminate in the same final common pathway, loss of the light-sensitive photoreceptors. There are few clinical treatments and none can reverse the loss of vision. Photoreceptor replacement by transplantation is proposed as a broad treatment strategy applicable to all degenerations. The past decade has seen a number of landmark achievements in this field, which together provide strong justification for continuing investigation into photoreceptor replacement strategies. These include proof of principle for restoring vision by rod-photoreceptor transplantation in mice with congenital stationary night blindness and advances in stem cell biology, which have led to the generation of complete optic structures in vitro from embryonic stem cells. The latter represents enormous potential for generating suitable and renewable donor cells with which to achieve the former. However, there are still challenges presented by the degenerating recipient retinal environment that must be addressed as we move to translating these technologies towards clinical application.

Neuronal remodeling in retinal circuit assembly, disassembly, and reassembly

“…There are two major approaches to replace lost neurons in retinal disease: replacement via cell transplantation [90–92], or induction of cell regeneration or transdifferentiation within the adult retina [93, 94]. Stem cell approaches are increasingly successful in generating different types of retinal neurons, as are techniques to ensure survival of both stem cells [90, 91] and differentiated cells [92] after transplantation.…”

“…Stem cell approaches are increasingly successful in generating different types of retinal neurons, as are techniques to ensure survival of both stem cells [90, 91] and differentiated cells [92] after transplantation. The challenge now is that these seeded neurons must be integrated into the surviving circuitry to re-establish lost connections.…”

Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina

“…Strong arguments have been made in favor of limiting glial remodeling because it impedes clinical interventions (Jones et al, 2012; Marc et al, 2007; Pearson, 2014) and may exacerbate cone loss. The evidence to date in GS is that its limited glial response to RD does not attenuate photoreceptor loss, but does coincide with apparent stability of inner retinal neurons.…”

Delivery strategies for treatment of age-related ocular diseases: From a biological understanding to biomaterial solutions

“…The barrier for success with photoreceptor transplantation is significantly higher than that of RPE as the photoreceptors must integrate into the retinal circuitry in order to achieve functional repair, whereas the RPE cells provide more of a supportive role to the photoreceptors. For this reason and the difficulty in attaining a pure population of photoreceptors for transplantation, photoreceptor progenitors have not been tested clinically to date [184].…”

“…degree of trauma caused by the delivery of cells can affect the inflammatory response and thus the success of the transplantation[145,184]. Currently there are two locations in the eye used for delivery: the subretinal space, which is more technically challenging and potentially disruptive, but is the location where the cells are lost; and the vitreous, which is less invasive and not as technically challenging, but requires cells to survive in the vitreous and then migrate to the retina.…”