eprintid: 10108968 rev_number: 26 eprint_status: archive userid: 608 dir: disk0/10/10/89/68 datestamp: 2020-10-09 07:45:05 lastmod: 2021-09-01 06:10:35 status_changed: 2020-10-09 07:45:05 type: thesis metadata_visibility: show creators_name: Claudio Ribeiro, Joana Filpa title: Retinal Repair for Macular Degeneration ispublished: unpub divisions: UCL divisions: A01 divisions: B02 divisions: C08 divisions: D09 note: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. abstract: Current treatments for macular degeneration, such as gene therapy, pharmacological approaches and neuroprotective approaches require the present of the target cells, the photoreceptors, in order to achieve a successful outcome. This leaves several patients, where the retinal degeneration is too advanced, without any viable therapeutic alternative. Photoreceptor transplantation aims to replace the lost cells, providing a potential option for such cases. For photoreceptor replacement to succeed, transplanted photoreceptors must mature and establish synaptic connection with the host retina. The remodeling of the host retina must be considered, as its interneurons and synaptic circuits rearrange following photoreceptor degeneration. Additionally, an ethical and renewable source is required. Studies have shown that mouse and human embryonic stem cells (ESC) can be differentiated to photoreceptor and transplanted into models of retinal dystrophy. However, no unambiguous evidence of synaptic connectivity and rescue of vision have been achieved. Here a detailed characterization of the remodeling events following photoreceptor lost in Aipl1-/- animals is described. Aipl1-/- were chosen due to the severe and fast emerging phenotype. As expected, typical features of remodeling were identified in these retinas and potential morphological elements were selected for analysis, following transplantation. The transplantation conditions, specifically the number of transplanted cells, were optimized using mouse ESC-derived photoreceptors. Here was no evident cell maturation or integration in the host’s synaptic circuit, following transplantation. Interestingly, when transplanting human (h) ESC-derived cones indication of such events was seen. To increase the period post-transplantation Aipl1-/- and Rd1, another well-established model of end-stage retinal degeneration, mice were crossed with immuno-compromised animals. Twelve weeks following transplantation into immuno-compromised Rd1 mice, hESC-derived cones matured and established functional synapses with the host retina, achieving rescue of vision. Alternative explanations for the rescue seen can be excluded due to the use non-functional human induced pluripotent (hiPS)-derived cones as a sham control. date: 2020-09-28 date_type: published oa_status: green full_text_type: other thesis_class: doctoral_open thesis_award: Ph.D language: eng thesis_view: UCL_Thesis primo: open primo_central: open_green verified: verified_manual elements_id: 1810899 lyricists_name: Claudio Ribeiro, Joana lyricists_id: JFCRI04 actors_name: Claudio Ribeiro, Joana actors_id: JFCRI04 actors_role: owner full_text_status: public pagerange: 1-1 pages: 355 event_title: UCL institution: UCL (University College London) department: Institute of Ophthalmology thesis_type: Doctoral citation: Claudio Ribeiro, Joana Filpa; (2020) Retinal Repair for Macular Degeneration. Doctoral thesis (Ph.D), UCL (University College London). Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10108968/13/PhD%20thesis%20Joana%20Ribeiro%20final_excluded%203rd-party%20material.pdf