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Gene-modified Organoids Aid the Development of Retinal Degenerative Disease Therapies

Review of “NRL-/- gene edited human embryonic stem cells (ESCs) generate rod-deficient retinal organoids enriched in S-cone-like photoreceptors” from STEM CELLS by Stuart P. Atkinson

The generation of retinal organoids from human pluripotent stem cells recapitulates many of the typical features of retinogenesis, including an organized multilayered tissue structure and long human developmental differentiation times; therefore, they represent an exciting means to study human retinal development and associated pathologies [1, 2].

In a recent STEM CELLS article [3], researchers led by Jane C. Sowden (UCL Great Ormond Street Institute of Child Health, London, UK) describe their use of human embryonic stem cell (ESC)-derived retinal organoids in the exploration of the role of neural retina leucine zipper (NRL) [4], a conserved transcription factor linked to the generation of rod photoreceptors and the development of the retinal degenerative disease retinitis pigmentosa [5]. Fascinatingly, Cuevas et al. now confirm that NRL expression mediates the formation of rod photoreceptors and that its absence induces the formation of organoids that contain only cone photoreceptors, a strategy that may prove useful for transplantation therapies for retinal degenerative diseases.

The authors employed CRISPR/Cas9-mediated gene-editing to create NRL-deficient ESCs (by introducing a biallelic nonsense mutation into the NRL gene), which they then differentiated into three-dimensional retinal organoids that self-organized into embryonic optic vesicles that recapitulate the natural histogenesis of rods and cone photoreceptors. While the NRL-deficient optical vesicles developed comparably to their wild-type ESC counterparts, displaying a laminated, organized retinal structure with markers of photoreceptor synaptogenesis, they lacked rod photoreceptors and the expression of photoreceptor markers directly or indirectly regulated by NRL. Instead, NRL-deficient optical vesicles presented with an abnormal number of rare primordial cone photoreceptors that expressed elevated levels of cone photoreceptor markers.

Overall, the researchers establish the value of using genetically modified ESCs to characterize retinal developmental events in humans and generate new disease models for in vitro study, given the known role for NRL in retinitis pigmentosa [5]. Perhaps more importantly, the huge numbers of rare primordial cone photoreceptors produced in NRL-deficient optical vesicles may find use in cone cell replacement transplantation therapies for retinal degenerative diseases [6], although the use of genetically modified human ESCs may represent a potential barrier to translation.

For more on how gene-modified ESCs may represent the forward for retinal degenerative diseases, stay tuned to the Stem Cells Portal!

References

  1. Mellough CB, Collin J, Khazim M, et al., IGF-1 Signaling Plays an Important Role in the Formation of Three-Dimensional Laminated Neural Retina and Other Ocular Structures From Human Embryonic Stem Cells. STEM CELLS 2015;33:2416-2430.
  2. Meyer JS, Howden SE, Wallace KA, et al., Optic Vesicle-like Structures Derived from Human Pluripotent Stem Cells Facilitate a Customized Approach to Retinal Disease Treatment. STEM CELLS 2011;29:1206-1218.
  3. Cuevas E, Holder DL, Alshehri AH, et al., NRL−/− gene edited human embryonic stem cells generate rod-deficient retinal organoids enriched in S-cone-like photoreceptors. STEM CELLS 2021;39:414-428.
  4. Swaroop A, Xu JZ, Pawar H, et al., A conserved retina-specific gene encodes a basic motif/leucine zipper domain. Proceedings of the National Academy of Sciences 1992;89:266.
  5. Bessant DAR, Payne AM, Mitton KP, et al., A mutation in NRL is associated with autosomal dominant retinitis pigmentosa. Nature Genetics 1999;21:355-356.
  6. Collin J, Zerti D, Queen R, et al., CRX Expression in Pluripotent Stem Cell-Derived Photoreceptors Marks a Transplantable Subpopulation of Early Cones. STEM CELLS 2019;37:609-622.