A major cause of hereditary human blindness, Retinitis Pigmentosa (RP), has been resolved in rat trials by researchers at the RIKEN Center for Biosystems Dynamics Research (BDR) in Japan. Degenerated rat retinas received transplants and removal of grafted cells, which resulted in improved connections to host retinas and better light-responsiveness.
Study leader Michiko Mandai said, “We have previously reported work using mouse embryonic- and induced pluripotent stem cell – (iPES)-derived retinas in a mouse model of retinal degeneration.”
However, the deputy project leader in the Laboratory for Retinal Regeneration at RIKEN BDR said, “As far as we know, this is the first report of the timed removal of particular grafted cells being shown to improve retinal function in an animal model using tissue from human stem cells.”
Since the retinal sheets were created from human stem cells, the novel feat can now be tested in human clinical trials, according to the study authors in the January 21, 2022 edition of iScience.
“Since retinal ganglion cells form optic nerves to send the signal to the brain, a higher light responsiveness could theoretically lead to improved sensitivity to light or better resolution in visual function. Genetic modification in human stem cell-derived retinas showed a substantial functional improvement [in light responsiveness], compared with wild-type graft retinas. Depending on the retinal network of the transplanted area, light responsiveness of retinal ganglion cells may be correlated with increased signaling to the brain, so could lead to an increased light sensitivity or better resolution. Additionally, we were able to observe detailed host-graft synapse formation in the absence of graft bipolar cells, which previously was difficult. A frequently asked question in retinal cell therapies concerns whether retinal ganglion cell responses are really originated from the graft photoreceptors. The presence of multiple synaptic markers at the host-graft cell contact site suggests formation of some synapses between these cells and indicates that graft photoreceptor light responses may well be transmitted to host retinal cells. We can now move forward to applying this strategy in clinical studies, which we expect to improve clinical outcomes and be generally useful in stem cell-based therapies targeting retinal degeneration. If the clinical grade ISL1-deleted stem cell-derived retinas can first pass extensive safety testing, including for tumorgenicity, we estimate that this may take 4-5 years. While we are currently targeting end-stage disease eyes with stem cell based therapy, we think this strategy could also be applied to those with remaining central vision, to help increase the pericentral visual field or delay disease progression,” Mandai said.
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