A5050082615- Retinal Development and Disorders
- Retinal Diseases and Treatments
- Photoreceptor and optogenetics research
- Glaucoma and retinal disorders
- Retinal Imaging and Analysis
- Retinal and Optic Conditions
- Ophthalmology and Visual Impairment Studies
- Neuroscience and Neural Engineering
- Ocular Disorders and Treatments
- RNA regulation and disease
- Virus-based gene therapy research
- Photochromic and Fluorescence Chemistry
- Retinal and Macular Surgery
- Retinoids in leukemia and cellular processes
- Retinopathy of Prematurity Studies
- Visual perception and processing mechanisms
- Cellular transport and secretion
- bioluminescence and chemiluminescence research
- Connexins and lens biology
- melanin and skin pigmentation
- CRISPR and Genetic Engineering
- Advanced Fluorescence Microscopy Techniques
- Ocular and Laser Science Research
- Genetic and Kidney Cyst Diseases
- Circadian rhythm and melatonin
University of Pennsylvania
2016-2025
Penn Presbyterian Medical Center
2016-2025
Visual Sciences (United States)
2021
Case Western Reserve University
2011
University of Florida
2009
Howard Hughes Medical Institute
2002-2007
University of Iowa Hospitals and Clinics
2000-2007
University of Washington
1998-2005
University of Miami
1992-2005
Hospital for Sick Children
2005
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...
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...
<h3>Purpose</h3> The Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) was developed to restore some vision patients blind as a result of retinitis pigmentosa (RP) or outer retinal degeneration. A clinical trial initiated in 2006 study the long-term safety and efficacy with bare no light perception resulting from end-stage RP. <h3>Design</h3> Prospective, multicenter, single-arm trial. Within-patient controls included nonimplanted fellow eye patients' native...
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...
<h3>Purpose</h3> Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due photoreceptor loss. rare disease, affecting only approximately 100 000 people in the United States. There no cure and approved medical therapy slow or reverse RP. The purpose this clinical trial was evaluate safety, reliability, benefit Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) restoring some visual function subjects completely blind from...
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...
Mutations in the gene encoding rhodopsin, visual pigment rod photoreceptors, lead to retinal degeneration species from Drosophila man. The pathogenic sequence cell-specific mutation of rods and cones remains unclear. To understand disease process man, we studied heterozygotes with 18 different rhodopsin mutations by using noninvasive tests cone function histopathology. Two classes expression were found, there was allele-specificity. Class A mutants severely abnormal across retina early life;...
Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause childhood blindness known as Leber congenital amaurosis (LCA). Retinal therapy restores vision blind canine and murine models LCA. Gene humans with LCA from RPE65 mutations may also have potential for success but only if retinal photoreceptor layer is intact, early-disease stage-treated animals. Here, we use high-resolution vivo microscopy quantify thickness human disease define relationship...
Mutations in ABCA4, which encodes a photoreceptor specific ATP-binding cassette transporter (ABCR), cause autosomal recessive forms of human blindness due to retinal degeneration (RD) including Stargardt disease. The exact disease sequence leading and vision loss ABCA4-RD is not known. Extrapolation from murine vitro studies predicts that two the earliest pathophysiological features resulting disturbed ABCR function man would be slowed kinetics retinoid cycle accelerated deposition...
Mutations in the retinal pigment epithelium gene encoding RPE65 are a cause of incurable early-onset recessive human degenerations known as Leber congenital amaurosis. Rpe65 -deficient mice, model amaurosis, have no rod photopigment and severely impaired physiology. We analyzed retinoid flow this then intervened by using oral 9- cis -retinal, attempting to bypass biochemical block caused genetic abnormality. Within 48 h, there was formation dramatic improvement physiology, thus demonstrating...
Recombinant adeno-associated virus (rAAV) is a promising vector for therapy of retinal degenerative diseases. We evaluated the efficiency, cellular specificity, and safety cell transduction in nonhuman primates after subretinal delivery an rAAV carrying cDNA encoding green fluorescent protein (EGFP), rAAV. CMV.EGFP. The treatment results efficient stable EGFP expression lasting >1 year. Transgene neural retina limited exclusively to rod photoreceptors. There neither electroretinographic nor...