A novel platform for minimally invasive delivery of cellular therapy as a thin layer across the subretina for treatment of retinal degeneration

Abstract

Incurable retinal degenerations affect millions worldwide. Stem cell transplantation rescued visual functions in animal models of retinal degeneration. In those studies cells were transplanted in subretinal "blebs", limited number of cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection sites. We developed a minimally-invasive surgical platform for drug and cell delivery in a thin layer across the subretina and extravascular spaces of the choroid. The novel system is comprised of a syringe with a blunt-tipped needle and an adjustable separator. Human bone marrow mesenchymal stem cells (hBM-MSCs) were transplanted in eyes of RCS rats and NZW rabbits through a longitudinal triangular scleral incision. No immunosuppressants were used. Retinal function was determined by electroretinogram analysis and retinal structure was determined by histological analysis and OCT. Transplanted cells were identified as a thin layer across the subretina and extravascular spaces of the choroid. In RCS rats, cell transplantation delayed photoreceptor degeneration across the entire retina and significantly enhanced retinal functions. No retinal detachment or choroidal hemorrhages were observed in rabbits following transplantation. This novel platform opens a new avenue for drug and cell delivery, placing the transplanted cells in close proximity to the damaged RPE and retina as a thin layer, across the subretina and thereby slowing down cell death and photoreceptor degeneration, without retinal detachment or choroidal hemorrhage. This new transplantation system may increase the therapeutic effect of other cell-based therapies and therapeutic agents. This study is expected to directly lead to phase I/II clinical trials for autologous hBM-MSCs transplantation in retinal degeneration patients.

A minimally invasive adjustable‐depth blunt injector for delivery of pharmaceuticals into the posterior pole

“…This study and our previous work (Rotenstreich et al. ) suggest that the novel injection system may potentially be used for safe and efficient delivery of cell therapy and pharmaceuticals into the posterior pole, in close proximity to the target retina and choroid. Our platform may enable new, more efficient treatment for posterior segment diseases.…”

“…In previous studies, we demonstrated the safety and efficacy of delivering stem cells into the EVSC compartment using this novel injector (Rotenstreich et al. ). In this study, we examined the efficacy and safety of delivering pharmaceuticals and nanotherapies into this compartment.…”

“…We developed a novel adjustabledepth blunt injector for minimally invasive delivery of therapeutics across the extravascular spaces of the choroid (EVSC) compartment that underlies the RPE, covering most of the surface of the back of the eye, including the central retina, without inserting any surgical tools under it. In previous studies, we demonstrated the safety and efficacy of delivering stem cells into the EVSC compartment using this novel injector (Rotenstreich et al 2015). In this study, we examined the efficacy and safety of delivering pharmaceuticals and nanotherapies into this compartment.…”

Long-Term Safety of Transplanting Human Bone Marrow Stromal Cells into the Extravascular Spaces of the Choroid of Rabbits

“…Transplanted cells were localized in a thin homologue layer, covering 87 ± 3% (mean ± SE) of the subretina surface 2 hours following transplantation [24, 25]. …”

“…This study established the rational for transplanting hBMSCs in the EVSC compartment as a possible treatment for AMD and RP. In subsequent studies, we demonstrated the efficient delivery of hBMSCs into the EVSC of rabbits using a novel injector [ 24 , 25 ].…”