Title: “A systematic review of cellular therapies for the treatment of limbal stem cell deficiency affecting one or both eyes."
Funder: Department of Health and Social Care

Abstract: Background: Limbal stem cell deficiency (LSCD) is a sight-threatening condition which results from damage to peripheral corneal tissue (i.e. limbus) that repairs and restores the front of the eye (i.e. cornea). For 30 years LSCD was treated by transplanting large limbal tissue from the healthy other eye (autograft) or from a donor (allograft). This approach may induce LSCD in the donor eye(16). Where an allograft is used the patient requires lifelong systemic immunosuppression to prevent graft rejection; however, this carries significant side-effect risks. In 1997, a new treatment was described which involved taking much smaller pieces of limbal tissue, expanding the stem cells in laboratory to produce an adequate amount of stem cells for transplantation and thus reducing the risk of iatrogenic LSCD to the donor eye. Stem cells from other parts of the body (e.g. oral mucosa) have also been used to treat bilateral LSCD using autologous cells(48). The safety and efficacy of this treatment is challenging to establish due to the intra- and inter-study heterogeneity such as the type of LSCD (partial or total); cause of LSCD; source of donor tissue; type of culture method; and variety of outcome measured(6). Human amniotic membrane (HAM) is non-immunogenic and has been extenisvely used, as a substrate, to grow stem cells ex vivo/culture system in laboratory prior to transplantation. HAM has the potential to replace potentially biohazardous animal products used in cell culture(19). To the best of our knowledge, there has not been such a rigorous assessment of publications concerning cell-based therapies for LSCD. Aims: To assess the impact of cell-based therapy on the management of LSCD, using a published validated outcome score if one can be identified. To summarise the current knowledge on the efficacy and safety of all cell therapy products available to treat LSCD. To summarise the published evidence on the cost-effectiveness of all forms of cell therapy for the treatment of LSCD. To identify the best methodology for use in a clinical trial of cellular therapies for LSCD. To establish which method of ex-vivo cultured stem cell transplant offers the best outcomes to treat both uni- and bilateral LSCD. Questioned to be addressed: Which donor stem cell source offers the best outcomes to treat both unilateral and bilateral LSCD? Which laboratory method of ex-vivo cultured stem cell transplant offers the best outcomes to treat both unilateral and bilateral LSCD? Which surgical technique for cellular transplantation offers the best outcomes to treat both unilateral and bilateral LSCD? Outcomes include: surgical complications; best corrected visual acuity; patient reported outcomes or quality of life outcomes; symptom relief; corneal surface reconstruction; need for further surgery such as corneal transplantation; costs; complications to the donor eye; complications to the recipient eye. Investigation plan: To complete a systematic review (and meta-analysis if possible) and report the findings according to PRISMA. To conduct a systematic search of databases including MEDLINE, Embase, ClinicalTrials.gov, and The Cochrane Library to identify randomised controlled trials (RCTs) as well as prospective and retrospective observational studies of LSCD treatment. To identify and review all published research on cellular therapies for LSCD to identify a promising methodology to use in a clinical trial. Benefits to patients: Maximising visual acuity and reducing chronic ocular pain after treatment of LSCD reduces patient disability and increases their likelihood to live independent lives and return to work. Benefits to NHS: Identification of the most efficacious cellular replacement in LSCD will support a cost effective management of the condition through widespread implantation and subsequent economies of scale for the NHS and will enable discontinuation of less efficacious and less cost-effective therapies for treatment of the disease.

Lay abstract: Limbal stem cell deficiency (LSCD) is a sight-threatening condition which results from damage to tissue that repairs and restores the outer most layer of cells coating the front of the eye. For 30 years this has been treated by transplanting large corneal tissue from the healthy other eye in cases of LSCD in one eye or from a donor (a living relative or deceased person). This approach may induce LSCD in the healthy eye. Where a donor is used the patient needs lifelong anti-rejection medicines but is still at risk of transplant rejection and medicine related complications. In 1997, a new treatment was described which involved taking much smaller pieces of corneal tissue, reducing the risk of causing LSCD, and growing the stem cells in laboratory to produce an adequate amount of stem cells for transplantation (5). Advances have also allowed the use of patient s own stem cells from other sites of the body which reduces the risk of causing LSCD in donor eyes and does not need anti-rejection medicines. One of the main barriers to translating this work for patient benefit is the lack of a single method in terms of defining which donor stem cell site is best and which laboratory and surgical techniques are best (6). We aim to conduct a systematic literature review to identify the best methodology for use in a clinical trial of cellular therapies for LSCD. &bull; We will search large biomedical research databases to identify relevant articles. &bull; Relevant research will be formally selected. &bull; Data from the research will then be extracted and summarised systematically. Findings will be shared with the scientific community through conference presentations and peer-reviewed publications and with the public and patients to further our common goal of developing cell therapy to cure blindness caused by LSCD worldwide.

Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: EYE