We have recently developed a new cell delivery system

We have recently developed a new cell delivery system that enabled the transplantation of hBM-MSCs as a thin layer across the extravascular spaces of the choroid in RCS rats. The graft covered most of the area of the back of the eye via a single injection with no retinal detachment or choroidal hemorrhages. Cell transplantation delayed photoreceptor degeneration throughout the whole retina and rescued retinal function for up to 5months in RCS rats (Tzameret et al., 2014). By contrast, when hBM-MSCs were injected intravitreally, they formed a large cell clamp in the vitreous cavity and retinal function was rescued for a shorter duration, up to 12weeks following transplantation (Tzameret et al., 2014). These findings suggested that the delivery method significantly affects therapeutic potential of transplanted cells, and that graft location, distance from the retina and graft surface area may be critical parameters for achieving effective treatment. In the present study we examined another delivery method for hBM-MSCs to the posterior eye: transplanting the order Concanamycin A in the epiretina. Transplantation of hBM-MSCs using this method resulted in photoreceptor rescue across most of the retina and significantly enhanced retinal function for up to 5months following cell transplantation.
Methods
Results
Discussion In this study we show that epiretinal transplantation of hBM-MSCs in RCS rats resulted in long-term preservation of retinal function and significantly delayed photoreceptor degeneration throughout the retina for up to 5months. Conventional intravitreal injection of stem cells results in cell clumps in the vitreous, since the enveloping membrane of the vitreous and its high viscous quality prevent the stem cells from spreading on the surface of retina and diffuse through the vitreous body. We have previously demonstrated that transplanting hBM-MSCs in clamps in the vitreous reduced their therapeutic effect, most likely since the secreted trophic factors need to diffuse through the vitreous and may fail to reach effective dosage in the retina (Tzameret et al., 2014). By contrast, the surgical procedure presented here involves vitreous separation from the retina to overcome the physico-chemical properties of the vitreous, allowing more effective cell diffusion and facilitating cell spreading in close proximity to the retina. Thus the epiretinal transplantation method enhances the therapeutic effect of hBM-MSCs compared with intravitreal injection. Epiretinal transplantation of hBM-MSCs could be identified in the vitreous cavity for at least 6weeks following transplantation (Fig. 2). By contrast when these cells were transplanted in the extravascular spaces of the choroid, transplanted cells could be identified in the host tissue only up to 2weeks following transplantation (Tzameret et al., 2014). Nevertheless, ERG recordings demonstrated similar therapeutic effect that lasted 5months following cell transplantation regardless of the delivery method. These findings suggest that the exosomes, trophic factors and immune system modulators secreted by the hBM-MSCs during the first two weeks following cell transplantation may be sufficient to slow down retinal degeneration for several months. The vitreous volume in the human eye is significantly larger than that of rats. Hence we predict that conventional intravitreal injection of hBM-MSCs will be even less effective in patients than in the rats. Currently there are four ongoing registered phase I/II clinical trials using hBM-MSCs for retinal and macular degeneration. In three of these trials cells are delivered by intravitreal injection [NCT01531348, NCT01914913, NCT02016508] (ClinicalTrials.gov.2014). In the fourth trial, different methods of cell injection are being compared (retrobulbar, subtenon, intravitreal, intraocular, subretinal and intravenous, [NCT01920867]) (ClinicalTrials.gov.2014). The results from these studies have not been reported yet, but based on our findings we predict that different delivery methods will affect the clinical outcome.