Outer Retinal Cell Replacement: Putting the Pieces Together

Systemic immunosuppression promotes survival and integration of subretinally implanted human ESC-derived photoreceptor precursors in dogs

“…Transplantation of PSC-derived RPE cells for the treatment of AMD and Stargardt’s macular dystrophy has now moved into clinical trials ( Wang et al., 2020 ). In contrast, progress with photoreceptor replacement still faces a number of challenges, including optimizing uniform delivery of a large number of donor cells, improving long-term survival of donor photoreceptors, promoting sufficient integration into the host retina, and establishing functional synaptogenesis to enable recovery of visual function ( Ludwig and Gamm, 2021 ). In addition, the avoidance of immune rejection of allogeneic transplants needs further optimization before clinical trials can be initiated ( Zhang et al., 2021 ).…”

“…Human embryonic stem cells (hESCs) or induced pluripotent stem cell (iPSC)-derived photoreceptor precursor cells (PRPCs) that develop into retinal organoids (ROs) are a promising source for regenerative experimental therapies to restore photoreceptor function ( Ludwig and Gamm, 2021 ). Cell replacement studies in rodents have shown restoration of visual function using either ESC- or iPSC-PRPCs ( Ribeiro et al., 2021 ; Tu et al., 2019 ), and several clinical trials in humans are exploring the use of allogenic and autologous cell therapies for photoreceptor replacement ( Wang et al., 2020 ).…”

“…Cell replacement studies in rodents have shown restoration of visual function using either ESC- or iPSC-PRPCs ( Ribeiro et al., 2021 ; Tu et al., 2019 ), and several clinical trials in humans are exploring the use of allogenic and autologous cell therapies for photoreceptor replacement ( Wang et al., 2020 ). However, exogenous photoreceptor cell replacement therapies face critical challenges ( Ludwig and Gamm, 2021 ), including the need to (1) successfully deliver large numbers of cells subretinally to cover a large area, (2) ensure long-term photoreceptor survival rate by preventing immune rejection, and (3) promote sufficient integration into the host retina to recover visual function ( Singh et al., 2018 ).…”

“…The dog offers unique advantages for advancing experimental retinal therapies ( Ludwig and Gamm, 2021 ). Multiple models of dogs with naturally occurring mutations in some of the genes responsible for several forms of human IRDs are available and exhibit similar biological, pathological, and functional deficits as those reported for the human disease ( Bunel et al., 2019 ).…”

A Microfluidic Eye Facsimile System to Examine the Migration of Stem-like Cells

“…Regenerative medicine offers the exciting promise to restore vision through cell replacement therapy, where stem and progenitor-like cells (SCs) are transplanted into the retinal host to replace damaged and/or degenerated neurons (reviewed in [ 13 , 14 , 15 , 16 ]). A classical model of functional integration relies upon transplanted cells to perform several complex behaviors [ 17 , 18 , 19 ] including: (i) surviving surgical insertion into a damaged, adult host [ 20 ]; (ii) Infiltrating endogenous neural networks to achieve desired cellular positioning [ 21 , 22 ]; (iii) Differentiating appropriately into targeted neuronal cell type(s) [ 23 ]; and (iv) Initiating new synapses with functional, native cells to re-establish vision [ 24 , 25 , 26 ].…”