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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).
The eye
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
This must not be confused with Leber optic atrophy (see later). Leber congenital amaurosis is a primary retinal disorder that is one of the most common causes of childhood blindness and is autosomal recessive in inheritance. The condition can be detected in early infancy by electroretinogram. Occasional families with associated cerebral and renal degeneration are known but do not overlap with the isolated form. There is extensive locus heterogeneity, with pathogenic variants found in a retinal homeobox gene (CRX) and a separate retinal epithelium protein gene (RPE65) among others. Gene therapy is being developed for CRX.
Gene therapy for Leber congenital amaurosis due to RPE65 mutation: prospects for human application
Published in A Peyman MD Gholam, A Meffert MD Stephen, D Conway MD FACS Mandi, Chiasson Trisha, Vitreoretinal Surgical Techniques, 2019
Keiser Nicholas W, Dejneka Nadine S, Maguire Albert M, Bennett Jean
Gene therapy holds great promise for the treatment of inherited disorders causing blindness. One such disorder is Leber congenital amaurosis (LCA), which accounts for 5% of all genetic retinal dystrophies.1,2 Individuals with this disorder are severely visually impaired as infants and have a normal-appearing fundus with an extremely low or undetectable electroretinogram (ERG).1 Frequently associated findings in cases of LCA that have been described are nystagmus, eye poking, and hyperopia.3,4 Fundus abnormalities develop over time and visual defects deteriorate further or remain stagnant. Recent success has been achieved in gene therapy treatment for the murine and canine models of LCA. This chapter discusses these model systems, the surgical techniques needed to deliver viral vectors carrying the correct gene to the subretinal space, and results to date.
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.
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
Leber congenital amaurosis 10 (LCA10, MIM 611755) is a severe retinal dystrophy, causing blindness/severe visual impairment at birth or during the first months of life. LCA10 is caused by mutations in the CEP290 gene, which encodes for a protein required for the correct localization of ciliary and phototransduction proteins in retinal photoreceptor cells. The impossibility to package the long CEP290 cDNA (7.4 kb) into a single AAV vector has delayed the development of gene replacement strategies for LCA10. However, because CEP290 is a multi-domain-structure protein, minigenes designed to maintain essential functional properties have been evaluated. For instance, Zhang and colleagues have identified a human CEP290 domain (miniCEP290580−1180) that could partially delay photoreceptor loss after subretinal administration of AAV8 in a mouse model of the disease [70]. Another study has favored a ‘transcomplementation’ strategy, reporting that the Cep290rd16 mutation could be complemented in trans by a C-terminal CEP290 fragment delivered via AAV8-subretinal injection, which improved visual behavior in test mice [105]. Finally, the use of inteins has also been explored at the experimental level: AAV2/8-CEP290 protein trans-splicing vectors have achieved reconstitution of the large CEP290 protein in the mouse retina, showing ameliorated retinal phenotypes [64]. However, human studies have not been reported to date.