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Futuristic Approaches in Vitreoretinal Surgery
Published in Pradeep Venkatesh, Handbook of Vitreoretinal Surgery, 2023
Degenerative diseases of the retina, involving the retinal pigment epithelium and photoreceptors, like retinitis pigmentosa, Leber’s congenital amaurosis [LCA], and Stargardt’s disease contribute significantly to the burden of low vision globally. Until a few decades ago, the mechanism of cell death in photoreceptors and retinal pigment epithelium was not known. However, studies on Royal College of Surgeons [RCS] rats have now shown that apoptosis is a predominant method. It has also been found that photoreceptor cell death often occurs secondary to a genetic defect in the neighbouring retinal pigment epithelial cells. It has been demonstrated that in transfected cell cultures and transgenic mouse lines, expression of certain genes can prevent apoptosis. Hence, for gene-mediated disease, advances in gene therapy may play a significant role in preventing, reversing, or retarding the degenerative process. Studies have also tried to precisely determine the nature of cell death in age-related macular degeneration [ARMD].
Clinical Perspectives on Gene Therapy for Retinal and Eye Diseases
Published in Yashwant Pathak, Gene Delivery, 2022
Devika S. Joshi, Gaurav M. Karve, Shrikant D. Joshi
Retinitis pigmentosa, also known as hereditary retinal dystrophy is a group of retinal disorders causing progressive loss of vision due to pigmentary changes in the retinal pigment epithelial layer. It exists in syndromic (occurring in association with systemic disorders, e.g., Usher’s syndrome) and non-syndromic forms. Historically, it has been an untreatable disease, but newer scientific advances like gene therapy, retinal implants, etc., have allowed good improvement in vision.
Comparative Anatomy and Physiology of the Mammalian Eye
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
The capillary layer of the choroid, the choriocapillaris, is found in the inner portion just below the retinal pigment epithelium (RPE). It is responsible for the nutrition of the RPE and the outer retina and, in some species, for the entire retinal nutrition. The capillaries form a lobular network and are comprised of typical fenestrated endothelial cells surrounded by a basal lamina that surrounds and is shared by pericytes and smooth muscle cells.3,33,115 These lobules are supplied by a central arteriole and are surrounded by a ring of postcapillary venules.33 These vessels are permeable to fluorescein and horseradish peroxidase. Between the choriocapillaris and the RPE is Bruch’s membrane which, when fully developed, is comprised of five layers: (1) the basement membrane of the RPE, (2) an inner collagenous zone, (3) elastic layer, (4) outer collagenous zone, and (5) the basement membrane of the capillary endothelial cells.3,33 In animals with a cellular tapetum the basal lamina of the RPE and the choriocapillaris fuse, obliterating the other three layers in the region overlying the tapetum.3 Venous drainage from the choroid occurs in four quadrants where blood collects in an ampulla and then drains via one of four vortex veins which penetrate the sclera.
Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders
Published in Expert Opinion on Biological Therapy, 2022
Lara Marrone, Paolo M. Marchi, Mimoun Azzouz
Stargardt disease (STGD1, MIM 248200) is a common form of hereditary recessive macular dystrophy caused by mutations in the ABCA4 gene, which encodes the retinal-specific ABCA4 protein involved in transporting retinoids from photoreceptors to the retinal pigment epithelium. Losing this protein leads to a progressive bilateral decline in central vision that begins in adolescence, accompanied by lipofuscin deposits around the macula. Because of the large size of the ABCA4 coding sequence (6.8 kb), dual AAV strategies have been explored to deliver the ABCA4 gene product for gene replacement therapy [100]. Subretinal administration of AAV2/8 using trans-splicing and hybrid vector strategies has shown efficient retinal pigment epithelium and photoreceptor transduction [29,30,101]. Intein vectors have also been used, particularly targeting mice, pigs and human retinal organoids. Although some of these studies have revealed amelioration of retinal phenotypes in STGD1 mouse models [29,64,102], the low transduction efficiencies as well as the aberrant production of truncated proteins from single AAV vectors have been two major limitations [103,104]. Including degradation sequences in the 5′-half-containing vector has successfully minimized the untoward generation of truncated proteins [30], achieving improved features that may prove beneficial for the clinical application of dual AAVs to target this disease.
An optometrist’s guide to the top candidate inherited retinal diseases for gene therapy
Published in Clinical and Experimental Optometry, 2021
Fleur O’Hare, Thomas L Edwards, Monica L Hu, Doron G Hickey, Alexis C Zhang, Jiang-Hui Wang, Zhengyang Liu, Lauren N Ayton
Retinitis pigmentosa can be characterised by photoreceptor dysfunction that is either primary (a gene critical for rod or cone cell function is mutated e.g. RHO in rod cells), or secondary (the mutation affects the function of a non-photoreceptor cell e.g. RPE65 for the retinal pigment epithelium),24 which subsequently affects rod and cone function, leading to photoreceptor degeneration.25 Retinitis pigmentosa is further classified as ‘non-syndromic’ if the condition is isolated, or ‘syndromic’ if associated with systemic anomalies such as Usher Syndrome, a leading cause of auditory and visual impairment.26,27 Additionally, other clinical categories may also be applied that relate to the temporal pattern of disease (i.e. rod-cone versus cone-rod versus cone, and stationary versus progressive).
A Wide Spectrum of Ocular Manifestations Signify Patients with Systemic Sclerosis
Published in Ocular Immunology and Inflammation, 2021
Gabriella Szucs, Zoltan Szekanecz, Zsuzsa Aszalos, Rudolf Gesztelyi, Judit Zsuga, Peter Szodoray, Adam Kemeny-Beke
Generalized vasculopathy plays an important role in the pathomechanism of SSc, and this fact is particularly supported by the large portion of cases with microvascular abnormalities in the retina and choroid (Figure 2C). In our study, different forms were found, ranging from mild retinal pigment epithelial atrophy to drusen or choroidal scar formation and severe age-related macular degeneration (AMD). The retinal blood vessel irregularities observed in SSc are highlighted by the finding of a possible relationship between SSc and ocular diseases that was first mentioned in 1953 in a case report by Agatston, who observed retinal cystoid bodies.36 However, it must be emphasized that the retinal and choroidal findings observed in SSc are declared equivocal in that their relatedness to the underlying disease cannot be excluded; nevertheless, some of them are expected to be related to age and systemic hypertension. Consequently, further clinical studies and histopathological evaluations are needed to verify or reject any such possible relationship.