Stem cells derived from the human brain and grown as neurospheres (HuCNS-SC) have been shown to be effective in treating central neurodegenerative conditions in a variety of animal models. Human safety data in neurodegenerative disorders are currently being accrued. In the present study, we explored the efficacy of HuCNS-SC in a rodent model of retinal degeneration, the Royal College of Surgeons (RCS) rat, and extended our previous cell transplantation studies to include an in-depth examination of donor cell behavior and phenotype post-transplantation. As a first step, we have shown that HuCNS-SC protect host photoreceptors and preserve visual function after transplantation into the subretinal space of postnatal day 21 RCS rats. Moreover, cone photoreceptor density remained relatively constant over several months, consistent with the sustained visual acuity and luminance sensitivity functional outcomes. The novel findings of this study include the characterization and quantification of donor cell radial migration from the injection site and within the subretinal space as well as the demonstration that donor cells maintain an immature phenotype throughout the 7 months of the experiment and undergo very limited proliferation with no evidence of uncontrolled growth or tumor-like formation. Given the efficacy findings and lack of adverse events in the RCS rat in combination with the results from ongoing clinical investigations, HuCNS-SC appear to be a well-suited candidate for cell therapy in retinal degenerative conditions.

Human retinitis pigmentosa results eventually in retinal ganglion cell (RGC) death, but how this occurs remains obscure. We have previously documented that in pigmented dystrophic Royal College of Surgeons (RCS) rats, photoreceptor degeneration is followed by retinal pigment epithelial (RPE) migration, formation of RPE-vascular complexes, and vascular displacement that causes RGC axonal compression and death. To investigate if phototoxic-induced photoreceptor degeneration is capable of causing similar pathologic events, we dilated the left pupil of pigmented nondystrophic RCS and Lister-Hooded rats and exposed them to light (3000 lux) for 72 hours. After various survival periods ranging between 0 hours and 21 months, the retinas were processed as whole mounts or in cross-sections. Two separate retinal degenerative events that may relate to differential light exposure across the retina were observed: an early arciform area of degeneration in the superotemporal retina and a delayed degeneration in the central and ventral retina. Although degeneration in the arciform area was always more severe and developed earlier (sensitive region), both of them showed quite comparable pathologic events to those described for dystrophic RCS rats. RGC axonal compression was seen as soon as 21 days after light exposure and RGC loss was seen 9 months after light exposure, mainly in the superotemporal retina, but also in the ventral retina. The results show that RGC loss in induced photoreceptor degeneration results from a similar series of events to those occurring as a consequence of inherited degeneration and therefore is not uniquely a property of inherited photoreceptor degeneration.

Engineered Schwann cells sustain retinal structure and function in the dystrophic RCS rat. Cells overexpressing GDNF or BDNF had a greater effect on photoreceptor survival than the parent line or sham surgery. This study demonstrates that ex vivo gene therapy and subsequent cell transplantation can be effective in preserving photoreceptors from the cell death that normally accompanies retinal degeneration.