4 YEAR PhD IN NEUROSCIENCE
Rachael A Pearson
Institute of Ophthalmology
Stem Cell Therapy and Retinal Degeneration
Retinal degenerations culminating in photoreceptor (PR) loss are the leading causes of untreatable blindness in the Western world. Clinical treatments are of limited efficacy, at best slowing disease progression. As such, there is a clear need for new therapeutic approaches. Gene therapy is effective in the treatment of inherited retinal disease. However, such strategies will be ineffective once degeneration has occurred. PR transplantation offers a complementary approach that could not only halt the progression of blindness but also potentially reverse it. In two landmark studies, we have demonstrated that, by using donor cells from early postnatal retina, PR cell transplantation is possible. The adult retina is capable of integrating transplanted cells & these cells develop unambiguous characteristics of mature PRs. Moreover, we demonstrated that the cells that possess this capacity to migrate & functionally integrate are post-mitotic PR precursors, rather than stem or progenitor cells (MacLaren & Pearson et al., Nature, 2006). Most importantly, we now have definitive evidence of restoration of rod-mediated visually guided behaviour in rod-deficient mice following transplantation (Pearson et al., Nature, 2012). Of critical importance was the finding that the amount of vision restored is critically dependent upon the number of cells that correctly integrated. Together, these establish a major proof-of-concept; that PR transplantation has the potential to improve not only retinal function but actually restore vision and provide strong justification for the continued research into photoreceptor transplantation strategies for the treatment of blindness. They also increase the need to find appropriate donor cells from non-fetal sources. Recent advances in stem cell technology have demonstrated the potential to generate photoreceptor precursor donor cells. In a remarkable recent study, Eiraku et al., have demonstrated that it is possible to essentially grow a retina in a culture dish. We have recently started to generate transplantation-competent rod precursors from ES cells (West et al., Stem Cells, 2012; Gonzalez et al., in prep).
Current areas of interest
1) Defining new strategies to restore cone-mediated vision. We have demonstrated that it is possible to restore vision mediated by rods but humans rely heavily upon cones for vision in daylight and colour-vision. For this reason, we aim to define new strategies for the restoration of cone-mediated vision by transplantation.
2) Determine the mechanisms of migration utilized by both rod and cone precursors in normal development and following transplantation. By understanding how the small proportion of cells transplanted manage to migrate into the recipient retina, we should be able to find ways to manipulate this migration and drive more cells into the recipient retina.
3) Determine strategies for breaking down barriers within the recipient retina. We have recently examined transplantation efficiency in a variety of models of retinal degeneration and found that disease type has a major impact on outcome (Barber et al., in review). On going work in my group aims to identify factors within the degenerating retina that impede (or enhance) transplanted cell integration and find ways to manipulate them to improve transplantation outcome (West et al., 2012; Pearson et al., 2010; West et al., 2008)
4) Determine whether purinergic signalling as an evolutionarily restricted signalling mechanism in the control of retinal stem cell proliferation. Unlike lower vertebrates, the mammalian retina lacks the ability to generate. Understanding the mechanisms behind these differences is crucial to knowing whether it might be possible to stimulate the mammalian retina to repair itself. We believe that the presence or absence of purinergic signaling may be important in determining this capability.
Techniques used in the lab: multi-photon, confocal and fluorescence microscopy, stem cell culture, calcium imaging, proliferation assays, viral vector production, molecular biology, transplantation, RNAi, multielectrode array recordings, electroretinogram recordings, intrinsic imaging of visual cortex, behavioural tests of vision.
Specific rotation projects can be discussed around any of the areas of investigation described above.
Pearson RA, Barber AC, Rizzi M, Hippert C, Xue T, West EL, Duran Y, Smith AJ, Chuang JZ, Azam SA, Luhmann UF, Benucci A, Sung CH, Bainbridge JW, Carandini M, Yau KW, Sowden JC, Ali RR. Restoration of vision after transplantation of photoreceptors. Nature. 2012 May 3;485(7396):99-103.
Pearson RA*, West EL*, Barker SE, Luhmann UFO, MacLaren RE, Barber AC, Duran Y, Smith AJ, Sowden JC, Ali RR. (2010) Long term survival of photoreceptors transplanted into the adult neural retina requires immune modulation Stem Cells. 2010 Nov;28(11):1997-2007
Lakowski J, Baron M, Bainbridge J, Barber A, Pearson RA, Ali RR, Sowden JC. (2010) Generation of New Cone and Rod Photoreceptors in models of Lebers congenital amaurosis by Transplantation of Crx-Positive Precursor Cells. Hum. Mol. Gen. 2010 Dec 1;19(23):4545-59.
Pearson RA*, MacLaren RE*, MacNeil A, Douglas RH, Salt TE, Akimoto M, Swaroop A, Sowden JC, Ali RR (2006). Retinal repair by transplantation of photoreceptor precursors. Nature 444(7116):203-7.
Pearson RA, Dale N, Llaudet E, Mobbs P (2005) ATP released via gap junction hemichannels from the pigment epithelium regulates neural retinal progenitor proliferation. Neuron. 46. 731-744