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Recombinant DNA Technology and Gene Therapy Using Viruses
Published in Patricia G. Melloy, Viruses and Society, 2023
LUXTURNA is a type of gene therapy used for patients with “retinal dystrophy” caused by mutations in RPE65. The specific disease involved is also known as Leber congenital amaurosis, which causes a deterioration of the retina leading to blindness. The drug was approved for use in 2017 and was the first in vivo gene therapy approved using an AAV vector (AAV2) in the United States (Anguela and High 2019; Russell et al. 2017; Ledford 2015; Wang, Tai, and Gao 2019; Dunbar et al. 2018; Li and Samulski 2020; Shahryari et al. 2019).
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
Leber’s congenital amaurosis is an inherited retinal disorder which causes severe vision loss in infancy. Patients usually present with nystagmus, sluggish or near-absent pupillary responses, severely decreased visual acuity, photophobia, and high hypermetropia. There is no definitive treatment or cure for this condition. LCA occurs due to mutation in the RPE65 gene, which encodes a key enzyme that is required for regeneration of visual chromophore in the retinal cycle. The deficiency of all-trans retinyl ester isomerase leads to LCA.
Basic genetics and patterns of inheritance
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Gene therapy involves insertion of normal copies of genes into individuals who have genetic diseases. This can potentially be accomplished by either somatic cell or germ cell gene therapy. Most work thus far has focused on somatic cell gene therapy. There are two ways to approach somatic cell gene therapy. Ex vivo gene therapy involves removing a patient’s cells from the body, inserting the normal gene copy into the cells, and then returning the cells to the body. In in vivo gene therapy, cells are treated while inside the patient’s body. For successful gene therapy, the cell requiring treatment must be easily accessible and relatively long-lived. Some of the earliest human gene therapy trials were performed for severe combined immune deficiency due to adenosine deaminase deficiency, using bone marrow stem cells. Other cells under consideration for therapy have included lymphocytes, hepatocytes, muscle cells, and respiratory epithelial cells. More recently, gene therapy for Leber’s congenital amaurosis has been accomplished by replacement of the defective gene locally to the retina of the eye. Types of genetic diseases that are amenable to somatic cell gene therapy are primarily autosomal recessive or X-linked disorders that result in almost total lack of normal protein. Reconstitution of even 5% to 10% of normal protein levels appears to be sufficient to treat these diseases. Dominant disorders that are caused by heterozygosity for mutant and normal genes (dominant-negative mutations) are not likely to be treatable by gene replacement; methods to block production of the mutant protein will be required.
Inhibition of Posterior Capsule Opacification by Adenovirus-Mediated Delivery of Short Hairpin RNAs Targeting TERT in a Rabbit Model
Published in Current Eye Research, 2023
Na He, Xiangxiang Zhang, Peiling Xie, Jialing He, Zhigang Lv
Gene therapy, a promising therapeutic strategy, has developed dramatically in recent decades and is offering hope for the treatment of many previously untreated eye diseases, especially inherited blindness.24,25 In recent years, several gene therapy clinical trials have been conducted for the treatment of age-related macular degeneration,26 Leber hereditary optic neuropathy,27 Stargardt dystrophy,28 and choroideremia.29 The approval of Luxturna for the treatment of Leber’s congenital amaurosis in the United States is a landmark achievement in the development of gene therapy.30 Concerning the prevention of PCO, Bao et al. transfected a recombinant adenoviral vector carrying dominant-negative ubiquitin, which is involved in cell proliferation and differentiation, into a rabbit model and found significant inhibition of LEC proliferation and reduction of PCO formation.31 In the present study, we also used recombinant adenovirus to deliver shRNA for gene silencing because the proliferation of LECs starts within 48 h after traumatic injury in rabbits, and adenoviruses can generate a more rapid onset of expression (at 48 h post-injection) than adeno-associated viruses. However, the strong immunogenicity of adenoviruses may cause inflammation of tissues, which was also observed in the present study. Therefore, we suggest that topical anti-inflammatory agents should be used for 4 weeks after surgery, as in this study.
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
Leber congenital amaurosis (LCA) is a severe congenital or early-onset form of non-syndromic retinal blindness characterized by the presence of a searching nystagmus, absence of normal pupillary responses, poor vision from infancy, and variable fundus appearance at birth. To date, 26 genes have been identified as causing an LCA phenotype, 23 autosomal recessive and 3 autosomal dominant (available: https://sph.uth.edu/retnet/sum-dis.htm#B-diseases, access 3/31/22). While most forms of LCA or severe-early childhood onset retinal dystrophy (SECORD) are non-syndromic, an admixture of those with systemic or neurologic disorders may present initially with isolated ocular features early in life. Molecular diagnosis helps to clarify those with potential syndromic involvement and inform surveillance strategies.
A patient with X-linked retinoschisis and exudative retinal detachment associated with a pathogenic hemizygous variant c.304c>T in RS1
Published in Ophthalmic Genetics, 2022
Nathália Nishiyama Tondelli, Beatriz Mello Mencaroni, Carolina Maria Barbosa Lemos, Jefferson Rocha de Sousa, Gabriel Castilho Sandoval Barbosa, André Marcelo Vieira Gomes, Mariana Matioli da Palma
Unilateral Coats-like exudative vasculopathy has already been reported in patients with retinitis pigmentosa (RP) due to the CRB1, CNGB1, RPGR, and TULP1 variants (18,23,24) that were tested for in our patient, highlighting the importance of genetic testing in Coats-like disorder. CRB1 pathogenic variants are strongly associated with Coats-like disease in patients with RP. It was suggested that patients who have a complete loss of function of CRB1 tend to have Leber congenital amaurosis. Patients with residual CRB1 function tend to have retinitis pigmentosa (RP) with para-arteriolar retinal pigment epithelium (PPRPE) and RP with Coats-like disease (24). Interestingly, our patient has residual RS1 function. Coats-like RP is not typically observed in siblings or parents of affected individuals, suggesting that other unknown genetic and environmental factors may influence this phenotype (18,24). More studies are necessary to explain this association.