A5075246209- Retinal Development and Disorders
- Retinal Diseases and Treatments
- Photoreceptor and optogenetics research
- Glaucoma and retinal disorders
- RNA regulation and disease
- Retinal and Optic Conditions
- Ocular Disorders and Treatments
- Connexins and lens biology
- melanin and skin pigmentation
- Retinopathy of Prematurity Studies
- Photochromic and Fluorescence Chemistry
- Genetic and Kidney Cyst Diseases
- Cellular transport and secretion
- Retinal Imaging and Analysis
- Virus-based gene therapy research
- Visual perception and processing mechanisms
- Ophthalmology and Visual Impairment Studies
- Retinoids in leukemia and cellular processes
- CRISPR and Genetic Engineering
- Neuroscience and Neural Engineering
- bioluminescence and chemiluminescence research
- Retinal and Macular Surgery
- Ocular and Laser Science Research
- Genetic Syndromes and Imprinting
- Hedgehog Signaling Pathway Studies
University of Pennsylvania
2015-2024
Penn Presbyterian Medical Center
2015-2024
Jacobs (United States)
2024
Philadelphia University
2022
Visual Sciences (United States)
2021
Institute of Genetics and Cancer
2014
Medical Research Council
2010-2014
University of Edinburgh
2014
University of Miami
1989-2011
Case Western Reserve University
2011
Leber congenital amaurosis (LCA) is a group of autosomal recessive blinding retinal diseases that are incurable. One molecular form caused by mutations in the RPE65 (retinal pigment epithelium-specific 65-kDa) gene. A recombinant adeno-associated virus serotype 2 (rAAV2) vector, altered to carry human gene (rAAV2-CBSB-hRPE65), restored vision animal models with deficiency. clinical trial was designed assess safety rAAV2-CBSB-hRPE65 subjects RPE65-LCA. Three young adults (ages 21–24 years)...
The RPE65 gene encodes the isomerase of retinoid cycle, enzymatic pathway that underlies mammalian vision. Mutations in disrupt cycle and cause a congenital human blindness known as Leber amaurosis (LCA). We used adeno-associated virus-2-based replacement therapy to treat three young adults with RPE65-LCA measured their vision before up 90 days after intervention. All patients showed statistically significant increase visual sensitivity at 30 treatment localized retinal areas had received...
To determine the safety and efficacy of subretinal gene therapy in RPE65 form Leber congenital amaurosis using recombinant adeno-associated virus 2 (rAAV2) carrying gene.Open-label, dose-escalation phase I study 15 patients (range, 11-30 years age) evaluated after injection rAAV2- vector into worse-functioning eye. Five cohorts represented 4 dose levels different strategies.Primary outcomes were systemic ocular safety. Secondary assayed visual function with dark-adapted full-field...
Genes associated with inherited retinal degeneration have been found to encode proteins required for phototransduction, metabolism, or structural support of photoreceptors. Here we show that mutations in a novel photoreceptor-specific homeodomain transcription factor gene (CRX) cause an autosomal dominant form cone-rod dystrophy (adCRD) at the CORD2 locus on chromosome 19q13. In affected members CORD2-linked family, highly conserved glutamic acid first position recognition helix is replaced...
DNA samples from 161 unrelated patients with autosomal dominant retinitis pigmentosa were screened for point mutations in the rhodopsin gene by using polymerase chain reaction and denaturing gradient gel electrophoresis. Thirty-nine found to carry 1 of 13 different at 12 amino acid positions. The presence or absence correlated 174 out 179 individuals tested 17 families. absent 118 control subjects normal vision.
The short- and long-term effects of gene therapy using AAV-mediated RPE65 transfer to canine retinal pigment epithelium were investigated in dogs affected with disease caused by deficiency. Results AAV 2/2, 2/1, 2/5 vector pseudotypes, human or cDNA, constitutive tissue-specific promoters similar. Subretinally administered vectors restored function 23 26 eyes, but intravitreal injections consistently did not. Photoreceptoral postreceptoral both rod cone systems improved therapy. In followed...
Significance The first retinal gene therapy in human blindness from RPE65 mutations has focused on safety and efficacy, as defined by improved vision. disease component not studied, however, been the fate of photoreceptors this progressive degeneration. We show that improves vision for at least 3 y, but photoreceptor degeneration progresses unabated humans. In canine model, same result occurs when treatment is stage equivalent to study shows need combinatorial improve short term also slow long term.
Retinal gene therapy for Leber's congenital amaurosis, an autosomal recessive childhood blindness, has been widely considered to be safe and efficacious. Three years after therapy, improvement in vision was maintained, but the rate of loss photoreceptors treated retina same as that untreated retina. Here we describe long-term follow-up data from three patients. Topographic maps visual sensitivity regions, nearly 6 two patients 4.5 third patient, indicate progressive diminution areas improved...
Human gene therapy with rAAV2-vector was performed for the RPE65 form of childhood blindness called Leber congenital amaurosis. In three contemporaneous studies by independent groups, procedure deemed safe and there evidence visual gain in short term. At 12 months after treatment, our young adult subjects remained healthy without vector-related serious adverse events. Results immunological assays to identify reaction AAV serotype 2 capsid were unchanged from baseline measurements. clinical...
Hereditary retinal blindness is caused by mutations in genes expressed photoreceptors or pigment epithelium. Gene therapy mouse and dog models of a primary epithelium disease has already been translated to human clinical trials with encouraging results. Treatment for common photoreceptor blindness, however, not yet moved from proof concept the clinic. We evaluated gene augmentation two blinding canine diseases that model X-linked form retinitis pigmentosa GTPase regulator ( RPGR ) gene,...
Rhodopsin, the visual pigment mediating vision under dim light, is composed of apoprotein opsin and chromophore ligand 11-cis-retinal. A P23H mutation in gene one most prevalent causes human blinding disease, autosomal dominant retinitis pigmentosa. Although cultured cell transgenic animal models have been developed, there remains controversy over whether they fully mimic phenotype; exact mechanism by which this leads to photoreceptor degeneration unknown. By generating knock-in mice, we...
Abstract CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric received ≤4 doses of intravitreal sepofarsen into worse-seeing eye. The primary objective was evaluate safety...
Crx is a novel paired-like homeodomain protein that expressed predominantly in retinal photoreceptors and pinealocytes. Its gene has been mapped to chromosome 19q13.3, the site of disease locus for autosomal dominant cone-rod dystrophy (CORDII). Analysis proband from family with CORD revealed an Arg41Trp substitution third residue CRX homeodomain. The sequence change cosegregated phenotype was not detected 247 normal controls. Recombinant containing showed decreased DNA binding activity....