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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
In 2017, the US FDA approved voretigene neparvovec (Luxturna TM, Spark Therapeutics Inc.) for the treatment of RPE65-associated LCA. The long-term sustained effects on safety and efficacy of AAV2-RPE65 gene delivery in biallelic RPE65-mediated LCA were assessed over a period of three years, with the initial improvements in visual function peaking at 6 to 12 months after injection. 9Longer term findings have shown that, despite improved function of surviving retina, the durability of benefit can be limited by progressive retinal degeneration.10
Comparative Anatomy and Physiology of the Mammalian Eye
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
While nutritional and toxic injury can result in damage to the retina, many species also exhibit hereditary retinal degeneration which must be differentiated from the acquired retinal degeneration. Hereditary degeneration of the retina has been described in dogs,134,154,155 cats,156,157 horses,158 rats,159,160 mice,161,162 and chickens.163,164
Practical approach to macular translocation with 360° peripheral retinectomy
Published in A Peyman MD Gholam, A Meffert MD Stephen, D Conway MD FACS Mandi, Chiasson Trisha, Vitreoretinal Surgical Techniques, 2019
John P Denny, Mark T Cahill, Sharon F Freedman, Cynthia A Toth
Vision loss in neovascular age-related macular degeneration (ARMD) results from abnormal tissue disturbing underlying supporting structures of the retina: the retinal pigment epithelium (RPE), Bruch’s membrane, and the choriocapillaris.1 The resultant lack of support and nutrition to the overlying retina causes secondary retinal degeneration and subsequent loss of visual function. This mechanism of disease is also found in other conditions with subfoveal neovascularization, such as ocular histoplasmosis and myopic degeneration. Macular translocation surgery is a procedure used to arrest vision loss and in some cases improve vision by rotating the fovea away from the underlying diseased structures to an area of healthy RPE and underlying tissue.
Dual phenotype: co-occurring Leber congenital amaurosis and familial exudative vitreoretinopathy: a case report
Published in Ophthalmic Genetics, 2023
Virginia Miraldi Utz, Jared J. Ebert, Diana S. Brightman, Brittany N. Simpson, Stefanie Benoit, Robert A. Sisk
IQCB1 encodes the protein nephrocystin-5, which is expressed in the connecting cilia of photoreceptor cells and the primary cilia of renal epithelial cells (https://doi.org/10.1038/ng1520). Thus, biallelic pathogenic variants in IQCB1 lead to a ciliopathy with both ocular and renal manifestations known as Senior Loken Syndrome 5 (SLS 5). The ocular findings include early-onset, severe retinal degeneration, and vision loss. The renal component is called juvenile nephronophthisis, and is a progressive cystic kidney disease characterized by polyuria, anemia, and decreasing kidney function that typically results in end-stage kidney disease in early adolescence (https://doi.org/10.1111/nep.13393). Hence, early nephrology involvement is imperative, and routine screening must be performed to detect early stages of renal disease.
Emerging gene therapy products for RPGR-associated X-linked retinitis pigmentosa
Published in Expert Opinion on Emerging Drugs, 2022
Cristina Martinez-Fernandez de la Camara, Jasmina Cehajic-Kapetanovic, Robert E. MacLaren
Development of gene therapy medicinal products is still a young field with many challenges that stand in the way of realizing their full potential. These include a dynamic regulatory environment, market access for these costly therapies, clinical long-term safety and efficacy which have yet to be established, provider and health-care economic disruption, manufacturing costs with variable yields and limited capacity and even patient access and recruitment for gene therapies targeting rare diseases. There are over 300 different genes that can cause retinal degeneration. The plan for gene therapy ophthalmology sector to develop treatments for each one of these diseases, presents unique challenges with huge health care and economic implications. Even when pathogenic variants are known, the fact that they affect very small populations, makes the clinical development pathway economically non-viable in many instances.
Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases
Published in Nutritional Neuroscience, 2021
Keisuke Hikosaka, Keisuke Yaku, Keisuke Okabe, Takashi Nakagawa
Many studies have demonstrated that NAD metabolism is involved in various retinal degenerative diseases (Table 4). Mutations in Nmnat1 were identified in patients with Leber congenital amaurosis 9 (LCA9), an inherited retinal degeneration characterized by infantile-onset vision loss [92–95]. The association of Nmnat1 mutations with cone and cone-rod dystrophies was also reported [96]. Mice with compound heterozygous Nmnat1 E257 K mutation, which was found in patients with LCA9, exhibited mild retinal degeneration [97]. However, the detailed mechanism underlying retinal degeneration remains to be elucidated. Reportedly, most of the mutated Nmnat1 proteins had similar or rather higher enzymatic activities compared with wild-type Nmnat1. Conversely, the secondary structure of mutated Nmnat1 proteins was relatively less stable than that of the wild-type protein, and they lost enzymatic activity after heat shock, suggesting that LCA-associated Nmnat1 mutations introduced higher susceptibility to stress conditions, causing protein unfolding and aggregation [98].