Overview
Human vision relies on two kinds of light-sensitive nerve cell in the retina at the back of the eye. Rod photoreceptor cells are used in dim light and night conditions, while cone photoreceptors are for seeing colour and fine detail in our central vision.
The leading cause of blindness in higher income countries is photoreceptor cell death in conditions that affect the retina. It’s permanent and there is no treatment that can give back lost vision. Sight loss is fastest and most severe when cones die.
Dr Sowden and team are trying to develop stem cell therapies to repopulate the retina. The idea is to transplant cells into the retina to replace the photoreceptors lost to illness.
Progress has been good and they have shown in mice that transplanted cells can become working rods. They have also had some success with cones but need to increase the numbers. So the aim of this project is to find out how.
Cone photoreceptor stem cell transplants could one day be a cure for blindness due to cone loss. Results from the study will help take the therapy towards clinical trials.
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Publications
- Lakowski, J. et al. Transplantation of Photoreceptor Precursors Isolated via a Cell Surface Biomarker Panel From Embryonic Stem Cell-Derived Self-Forming Retina. Stem Cells 33, 2469–2482 (2015).
- Chapter 4 - Restoring Vision to the Blind: Stem Cells and Transplantation. Translational Vision Science & Technology 3, 6 (2014).
- ESC-Derived Retinal Pigmented Epithelial Cell Transplants in Patients: So Far, So Good: Cell Stem Cell. (2014).
- Warre-Cornish, K., Barber, A. C., Sowden, J. C., Ali, R. R. & Pearson, R. A. Migration, Integration and Maturation of Photoreceptor Precursors Following Transplantation in the Mouse Retina. Stem Cells Dev 23, 941–954 (2014).
- Gonzalez-Cordero, A. et al. Photoreceptor precursors derived from three-dimensional embryonic stem cell cultures integrate and mature within adult degenerate retina. Nat Biotech 31, 741–747 (2013).
- Boucherie, C. et al. Brief Report: Self-Organizing Neuroepithelium from Human Pluripotent Stem Cells Facilitates Derivation of Photoreceptors. STEM CELLS 31, 408–414 (2013).
- West, E. L. et al. Defining the Integration Capacity of Embryonic Stem Cell-Derived Photoreceptor Precursors. STEM CELLS 30, 1424–1435 (2012).
- Pearson, R. A. et al. Restoration of vision after transplantation of photoreceptors. Nature 485, 99–103 (2012).
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Scientific summary
Using Crx-positive precursors for cone photoreceptor replacement
Degenerative diseases of the retina are the leading cause of untreatable blindness in the developed world. Cone photoreceptors make up 5% of photoreceptors and provide high acuity daylight and colour vision. Many retinal diseases lead to blindness by either directly affecting cones, or through secondary cone loss, after extensive rod photoreceptor death. Cone loss causes severe deterioration of vision, whereas rod death initially causes night blindness. As the human retina has no mechanism of regeneration, the loss of photoreceptors is irreversible. Replacement of lost photoreceptors by transplantation represents a promising therapeutic approach, as a new photoreceptor only needs to re-establish a single synaptic connection to the inner retina.
The research group has developed a strategy for effective rod transplantation in mice that improves dim light sensitivity and recently they demonstrated that cone transplantation is also feasible. Small numbers of cones were found after transplantation of embryonic Crx-expressing photoreceptor precursors. This project aims to identify strategies to increase the efficiency of cone photoreceptor transplantation in mice and to prove that transplanted cells develop authentic features by electron microscopy analysis of connections with the host retina.
It will test (i) whether cone integration is enhanced in the cone depleted retina, (ii) whether altering the recipient environment to mimic the thyroid hormone levels of the developing retina enhances cone integration, (iii) whether the rod-rich adult environment or rod donor populations impede new cone integration and differentiation. This study will identify conditions for effective cone transplantation essential for the development of retinal stem cell therapy for blindness.