Age related macular degeneration (AMD) is a leading form of irreversible blindness. iMacular Regeneration LLC (iMac Regen) will introduce a novel tissue support structure (macular O-rings or MORs), made from a biocompatible, implantable material (nitinol or nickel-titanium alloy). The surgical device (MOR) will be tested both ex-vivo and in-vivo for proof of concept in this phase I STTR study. The device will support and protect donor tissue, reconstruct the degenerating tissue in the submacular space, enable translocation of autographs, and/or potentially other transplants or three-dimensional tissue organoids into the submacular space. This surgical device represents a critical unmet need in the current approach for regenerative medicine that addresses macular disease. Currently, many researchers are attempting to replace a portion of the damaged supporting tissues. For example, some investigators are injecting dissociated retinal pigment epithelium (RPE) or sheets of RPE monolayers alone or grown on synthetic substrates, some from embryonic or adult progenitor stem cells. Attempts to inject free-floating stem cells directly into the subretinal space to replace or support existing RPE have been attempted with limited success. The iMac Regen approach is unique and serves as a platform technology for many forms of tissue or cellular transplantation into the submacular space. MORs provide a biocompatible perimeter scaffold, much like a frame to support a painting. Thus, the MORs facilitate surgical manipulation and minimize tissue injury for the delicate, three-dimensional, choroid-Bruch's-RPE (CBR) tissue transplants used in translocation surgery. Our current proposal is to test a new GMP (good manufacturing processes) device ex-vivo and ensure proper donor tissue engagement. Then, we will translocate an autologous graft (a graft harvested from the same eye) in the live pig model. The autologous graft eliminates the risk of immune-mediated graft rejection. Using this regenerative medicine approach, the goal is to rescue damaged macular photoreceptors (MPRs) and restore their function before MPRs are permanently lost to advanced forms of AMD. This novel surgical device is proposed for those at or near the end-stages of dry or wet AMD as well as other forms of macular degeneration. The three-dimensional CBR graft represents an organoid that has all of the necessary cellular, membrane, and vascular components to provide the necessary blood flow, nutritional, and visual cycle support required by the MPRs. Studies from Europe have shown that transplant healthy CBR auto-graft tissue in humans inhibits abnormal angiogenesis wet AMD. The circumferential configuration (frame) of our device allows for tissue support without directly interfering with blood flow to the critical central region of the tissue graft. Loss of function in AMD results from damaged CBR tissue and occurs at the end-stages of both the wet and dry forms of AMD, thus leading to MPR death and blindness. The MORs are made from nitinol, a biocompatible, non-magnetic, implantable structure that has identical material as that used for decades for intra-arterial, coronary artery stents. The MORs serve 1) as a structural support for CBR donor graft, 2) to enable surgical manipulation of a delicate CBR graft, and 3) minimize CBR tissue shrinkage and injury. We predict that the result of our work will be regeneration of dying MPRs and inhibition of choroidal angiogenesis. Milestones include: 1) demonstration of the ability of the GMP device to attach and support donor tissue, 2) biocompatibility of nitinol in the subretinal space (with limited fibrosis), 3) in-vivo donor CBR tissue engraftment with vascularization, 4) functional results using electrophysiology, and 5) histologic verification in conjunction with two ophthalmic pathologists at the Mayo Clinic for: a) biocompatibility, b) graft vascularization, c) tissue reaction (scarring), and d) viable overlying MPRs. We are working toward commercialization through a feasibility process with supporting proof of concept for the newly manufactured GMP device (plus derivative instruments) in phase I STTR. We anticipate some minor device modifications based on these studies. Required IDE (Investigational Device Exemption) quality data in preparation for an audit will be acquired as we proceed along a 510K regulatory pathway and into phase II of the STTR funding mechanism.
Public Health Relevance Statement: Narrative We will test a novel surgical device that represents a platform technology to transplant donor tissue grafts that support macular function, replace damaged submacular tissues, regenerate macular photoreceptors and inhibit abnormal choroidal angiogenesis. This technology will address a critical unmet need in the treatment of advanced age related macular degeneration, a leading, worldwide cause of irreversible blindness.
Project Terms: 3-Dimensional; Address; Adult; advanced disease; Age related macular degeneration; Agreement; Allografting; Anatomy; angiogenesis; Animal Model; Asses; Autologous; Autologous Transplantation; base; bevacizumab; Biocompatible Materials; biomaterial compatibility; Blindness; Blood flow; Blood Vessels; Bruch's basal membrane structure; Businesses; Cell Death; Cells; Cellular Membrane; Cessation of life; Choroid; choroidal angiogenesis; Cicatrix; Clinic; Closure by clamp; commercialization; Coronary artery; Data; Data Quality; design; Devices; Dimensions; Disease; disorder of macula of retina; Donor person; Effectiveness; Elderly; Electrophysiology (science); Embryo; embryonic stem cell; Engineering; Engraftment; Ensure; Europe; Evidence based treatment; Exudative age-related macular degeneration; Eye; Family suidae; Fibrosis; Funding Mechanisms; Future; Goals; Graft Rejection; Harvest; heat injury; Histologic; Histopathology; Human; Immune; implantation; in vivo; induced pluripotent stem cell; Injury; innovation; instrument; instrumentation; intravitreal injection; Investigation; Legal patent; Letters; Licensing; loss of function; macula; Macular degeneration; manufacturing process; Mediating; Mediation; Memory; Minor; Modeling; Modification; monolayer; Natural regeneration; nitinol; nonhuman primate; novel; Nutritional; off-patent; Operative Surgical Procedures; Organoids; Outcome Measure; Pathologist; Patients; Phase; Phase I Clinical Trials; Photoreceptors; Preparation; preservation; Process; progenitor; prototype; Publishing; Quality Control; Reaction; Regenerative Medicine; Regulatory Pathway; Reporting; Research Personnel; response; retina blood vessel structure; Retinal; retinal progenitor cell; Risk; scaffold; Shapes; Small Business Technology Transfer Research; Stem cells; Stents; Structure; Structure of retinal pigment epithelium; success; Surgical complication; Techniques; technological innovation; Technology; Testing; Thinness; Tissue Donors; Tissue Grafts; Tissue Transplantation; Tissues; titanium nickelide; Transplantation; Transplanted tissue; Vascular Endothelial Growth Factors; vascular factor; Vascularization; visual cycle; Work; Xenograft procedure
