Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors

Abstract

Summary Age-related macular degeneration and other macular diseases result in the loss of light-sensing cone photoreceptors, causing irreversible sight impairment. Photoreceptor replacement may restore vision by transplanting healthy cells, which must form new synaptic connections with the recipient retina. Despite recent advances, convincing evidence of functional connectivity arising from transplanted human cone photoreceptors in advanced retinal degeneration is lacking. Here, we show restoration of visual function after transplantation of purified human pluripotent stem cell-derived cones into a mouse model of advanced degeneration. Transplanted human cones elaborate nascent outer segments and make putative synapses with recipient murine bipolar cells (BCs), which themselves undergo significant remodeling. Electrophysiological and behavioral assessments demonstrate restoration of surprisingly complex light-evoked retinal ganglion cell responses and improved light-evoked behaviors in treated animals. Stringent controls exclude alternative explanations, including material transfer and neuroprotection. These data provide crucial validation for photoreceptor replacement therapy and for the potential to rescue cone-mediated vision.

Sensory Transduction in Photoreceptors and Olfactory Sensory Neurons: Common Features and Distinct Characteristics

“…In addition, while gene therapy has provided some very exciting early results in treating visual disorders, a lot more work remains to be done before this approach will be ready for prime time (Garafalo et al, 2020). The recent development of retinal organoids is another exciting and rapidly growing area, which can contribute to our understanding of retinal development, gene regulation, and could provide the basis for future therapies (Ribeiro et al, 2021). Finally, the great diversity of phototransduction proteins mutations that cause visual disorders and blindness necessitates the development of gene-independent therapies for retinal disorders, whether based on common gene regulatory factors (Montana et al, 2013) or biological factors promoting photoreceptor survival (Orban et al, 2018).…”

Inducible Pluripotent Stem Cells to Model and Treat Inherited Degenerative Diseases of the Outer Retina: 3D-Organoids Limitations and Bioengineering Solutions

“…The number of donor photoreceptor precursors transplanted into the SRS may represent an important variable in the outcome of regenerative approaches to cure IRD [ 104 ]. It is presently unclear how the number of grafted cells (an extrinsic factor) may affect cone OS maturation, but the finding may lead to a significant paradigm change in transplantation work, which has so far mostly focused on the identification of improved sorting criteria to select optimal engrafting donors and discard inappropriate cells.…”

“…The similar engraftment yields with different and progressively more selective sorting criteria challenge the notion of an optimal maturation stage for engrafting and point to a role for stage-independent mechanisms. In line with this notion, the successful engraftment of donor cone precursors generated from hiPSC-derived ROs upon transplantation in an end-stage model of retinal degeneration has recently been achieved [ 104 ], with donor human cone precursors becoming light-responsive and establishing synaptic connection with postsynaptic cells has recently been achieved [ 104 ]. An important difference with previous transplantation work, where cone precursors survived in the SRS but failed to mature OSs, was the increased donor cell number (5 × 10 5 cells/1.5 µL) transferred to the SRS [ 104 ] compared to previous studies (1 × 10 5 –2.5 × 10 5 cells/1–2 µL, see Table 1 in [ 62 ]).…”

“…In line with this notion, the successful engraftment of donor cone precursors generated from hiPSC-derived ROs upon transplantation in an end-stage model of retinal degeneration has recently been achieved [ 104 ], with donor human cone precursors becoming light-responsive and establishing synaptic connection with postsynaptic cells has recently been achieved [ 104 ]. An important difference with previous transplantation work, where cone precursors survived in the SRS but failed to mature OSs, was the increased donor cell number (5 × 10 5 cells/1.5 µL) transferred to the SRS [ 104 ] compared to previous studies (1 × 10 5 –2.5 × 10 5 cells/1–2 µL, see Table 1 in [ 62 ]). These findings hint to a role for cell–cell contacts or short-range diffusing molecules in affecting maturation of grafted cells in the SRS.…”

Retinal Stem/Progenitor Cells Derived From Adult Müller Glia for the Treatment of Retinal Degeneration

“…Various sources of stem and progenitor cells, including Müller glia (MG), fetal retinal progenitor cells, ciliary epithelium-derived stem cells, umbilical tissue-derived stem cells, bone marrow-derived mesenchymal stem cells, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have been studied for their potential to rescue retinal degeneration ( Canto-Soler et al, 2016 ). The different types of stem and progenitor cells may rescue or restore vision via two broad mechanisms: (1) Replacement of lost cellular populations, e.g., photoreceptors or retinal pigment epithelium ( Gonzalez-Cordero et al, 2017 ; Zhao et al, 2017 ; Ribeiro et al, 2021 ); (2) Neuroprotection through general immune-modulatory or neuroprotective effects, which may occur directly via material transfer, or indirectly in a paracrine fashion ( Pearson et al, 2016 ; Singh et al, 2016 ; Nickerson et al, 2018 ). This review will focus on the therapeutic potential of MG and their derivatives.…”