Scalable production of RPE cells from induced pluripotent stem cell under GMP conditions for cellular replacement therapy of the dry form of AMD

Age related macular degeneration (AMD) is the leading cause of blindness in people over the age of 60 in the western world and each year the problem increases. AMD results in the central portion of vision being lost making it impossible to appreciate fine detail. AMD is associated with defects of the retinal support cells - the retinal pigment epithelial cells (RPE). The rods and cones (the photoreceptors) in the retina, which are the light sensitive cells, depend for their survival on the normal functioning of these cells, and so failure of these cells leads to progressive loss of vision and eventual blindness.
There is currently no treatment which prevents the development of AMD. However there has been some success for certain forms of AMD with a range of interventions, but these approaches are only suitable for certain patients and are often only temporary.
Our aim is to produce a cell replacement therapy from stem cells derived from patients themselves which are effective in replacing dysfunctional RPE found in AMD which will lead to a surgical therapy capable of stabalising and restoring vision in the vast majority of patients. We plan to develop, over three years, the necessary process of producing stem cells derived from patient skin samples and to turn these stem cells into RPE. We will test the safety and efficacy of these cells ready for use in patients. The goal is to submit a clinical trial application at the end of this project for these patient derived eye cells to initiate a Phase I/II clinical trial.

Stem cells can be differentiated from somatic cells by reprogramming with multiple factors which have the capability to be pluripotent. Forced expression of four transcription factors, Oct4, Sox2, Myc and Klf4, can reprogramme these cells to ESC-like cells with pluripotent qualities, termed induced pluripotent stem cells (iPSCs). This can be achieved using different combinations of transcriptions factors, such as Oct4, Sox2, Nanog and Lin28, which avoids the use of Myc, a known proto-oncogene. The goal of this project is to produce iPSC's which could be used therapeutically and manufactured under cGMP processes. We will then use clinically approved protocols to generate eye-like cells from iPSCs. We will manufacture retinal pigmented (RPE) cells for therapeutic replacement of these cells for the dry form of age-related macular degeneration. The iPSC-derived RPE cells form monolayers that exhibit polarity, form tight junctions, express genes vital to the visual cycle and are able to phagocytose. Transplantation of iPSC-derived RPE into animal models of retinal degeneration has been shown to improve visual function. This will produce the data to enable the submission of a clinical trial application.

There are a number of groups who will benefit apart from those directly involved in the project. There is a global goal to establish whether induced pluripotent stem cells could be used therapeutically. Questions still need to be addressed so both academia, industry and health services will benefit from the use of this technology. Equally, patient advocates and foundations funding specific diseases need confidence that this route will deliver.

For those involved in the research, enhancing research capacity, skills and knowledge base will be beneficial. Interactions with UK regulators (MHRA, EAG, NRES-GTAC) will mould organisational structures and practises. This will enhance knowledge and skills of public and private sectors organisations. It will be a major component to attract investment and involvement from industry through and including Catapult Cell Therapy. Finally, a number of innovative technologies and cross-disciplinary approaches will be developed maintaing the UK's profile in this fast developing arena.