Human Embryonic Stem Cell-Derived Retinal Pigment Epithelium Transplantation in Advanced Neovascular Age-Related Macular Degeneration

Age-related macular degeneration (AMD) remains one of the leading causes of permanent vision impairment worldwide. It is a disorder of the central retina that manifests with irreversible cell loss, primarily affecting the retinal pigment epithelium (RPE) and subsequently the retina and choroid, leading to blindness through atrophy or neovascularization and exudation. Current treatments are only able to suppress the progression of the early and moderate neovascular AMD, mainly by controlling leakage and haemorrhage, while there is no established therapy for the atrophic type or the advanced neovascular type. RPE transplantation strategies have been attempted with promising outcomes; however, their operational complexity combined with the large patients’ volume has underlined the need for more accessible cell sources and a more feasible surgical paradigm. This thesis aims to examine the feasibility, safety and efficacy of transplantation of a human Embryonic Stem Cell (hESC)-derived RPE sheet in patients with severe neovascular (n) AMD. A fully differentiated hESC-RPE monolayer on a coated synthetic basement membrane (BM) has been bioengineered ex vivo and, using a purpose-designed surgical tool, has been implanted in the subretinal space of two patients with nAMD and acute vision decline. Systemic immunosuppression was administered during the peri- operative periods, while only local, intra-ocular steroids were given for the longer term. The patients were followed-up in a prospective study to assess the safety, and the structural and functional outcomes of this strategy for two years post-operatively. Both subjects demonstrated good safety outcome with no signs of local or distal tumorigenicity or uncontrolled proliferation from the implanted cells. Both showed reconstruction of the RPE-BM complex sufficient to support the retinal structure and the rescue and preservation of the photoreceptors, during the study period. Furthermore, both patients showed significant gain in their visual function, in terms of fixation, retinal light sensitivity, visual acuity and reading speed, maintained for two years. Most importantly, in both cases there was a clear co-localisation of the structural support, provided by the transplant, with the areas of functional improvement. The work in this thesis provides proof that the reconstruction of the RPE using hESC on synthetic BM can rescue and preserve the retinal structure and function over the long term, in severe neovascular AMD

Structural and Functional Characteristics of Color Vision Changes in Choroideremia

Color vision is considered a marker of cone function and its assessment in patients with retinal pathology is complementary to the assessments of spatial vision [best-corrected visual acuity (BCVA)] and contrast detection (perimetry). Rod-cone and chorioretinal dystrophies—such as choroideremia—typically cause alterations to color vision, making its assessment a potential outcome measure in clinical trials. However, clinical evaluation of color vision may be compromised by pathological changes to spatial vision and the visual field. The low vision Cambridge Color Test (lvCCT) was developed specifically to address these latter issues. We used the trivector version of the lvCCT to quantify color discrimination in a cohort of 53 patients with choroideremia. This test enables rapid and precise characterization of color discrimination along protan, deutan, and tritan axes more reliably than the historically preferred test for clinical trials, namely the Farnsworth Munsell 100 Hue test. The lvCCT demonstrates that color vision defects—particularly along the tritan axis—are seen early in choroideremia, and that this occurs independent of changes in visual acuity, pattern electroretinography and ellipsoid zone area on optical coherence tomography (OCT). We argue that the selective loss of tritan color discrimination can be explained by our current understanding of the machinery of color vision and the pathophysiology of choroideremia

Bilateral Hypertensive Retinopathy Complicated with Retinal Neovascularization: Panretinal Photocoagulation or Intravitreal Anti-VEGF Treatment

Purpose: To present the case of a patient with bilateral hypertensive retinopathy complicated with retinal neovascularization who received anti-VEGF intravitreal injection in one eye and panretinal photocoagulation (PRP) in the fellow eye. Methods: A 33-year-old male patient presented with gradual visual loss in both eyes for the last 5 months. At that time, he was examined by an ophthalmologist and occlusive retinopathy due to malignant systematic hypertension was diagnosed. He was put on antihypertensive treatment but no ophthalmic treatment was undertaken. At presentation, 5 months later, best-corrected visual acuity (BCVA) was 0.1 in the right eye (RE) and 0.9 in the left eye (LE). Fundus examination was compatible with hypertensive retinopathy complicated with retinal neovascularization. Fluorescein angiography (FFA) revealed macular ischemia mainly in the RE and large areas of peripheral retinal ischemia and neovascularization with vascular leakage in both eyes. The patient was treated with two anti-VEGF (ranibizumab) injections with 2 months interval in the RE and PRP laser in the LE. Results: Follow-up examination after 12 months showed mild improvement in BCVA, and FFA documented regression of retinal neovascularization in both eyes. Conclusion: Hypertensive retinopathy can be rarely complicated with retinal neovascularization. Treatment with PRP can be undertaken. In our case, the use of an intravitreal anti-VEGF agent seemed to halt its progression satisfactorily

Deep Iterative Vessel Segmentation in OCT Angiography

This paper addresses retinal vessel segmentation on optical coherence tomography angiography (OCT-A) images of the human retina. Our approach is motivated by the need for high precision image-guided delivery of regenerative therapies in vitreo-retinal surgery. OCT-A visualizes macular vasculature, the main landmark of the surgically targeted area, at a level of detail and spatial extent unattainable by other imaging modalities. Thus, automatic extraction of detailed vessel maps can ultimately inform surgical planning. We address the task of delineation of the Superficial Vascular Plexus in 2D Maximum Intensity Projections (MIP) of OCT-A using convolutional neural networks that iteratively refine the quality of the produced vessel segmentations. We demonstrate that the proposed approach compares favourably to alternative network baselines and graph-based methodologies through extensive experimental analysis, using data collected from 50 subjects, including both individuals that underwent surgery for structural macular abnormalities and healthy subjects. Additionally, we demonstrate generalization to 3D segmentation and narrower field-of-view OCT-A. In the future, the extracted vessel maps will be leveraged for surgical planning and semi-automated intraoperative navigation in vitreo-retinal surgery