A5052697690- Retinal Development and Disorders
- Retinal Diseases and Treatments
- Virus-based gene therapy research
- Photoreceptor and optogenetics research
- CRISPR and Genetic Engineering
- Mitochondrial Function and Pathology
- Retinal and Optic Conditions
- bioluminescence and chemiluminescence research
- RNA regulation and disease
- Herpesvirus Infections and Treatments
- Glaucoma and retinal disorders
- Ocular Disorders and Treatments
- interferon and immune responses
- Retinopathy of Prematurity Studies
- RNA Interference and Gene Delivery
- Viral Infectious Diseases and Gene Expression in Insects
- Photochromic and Fluorescence Chemistry
- Photosynthetic Processes and Mechanisms
- Cytomegalovirus and herpesvirus research
- Endoplasmic Reticulum Stress and Disease
- Connexins and lens biology
- Advanced Glycation End Products research
- Retinal and Macular Surgery
- Ubiquitin and proteasome pathways
- Corneal Surgery and Treatments
University of Florida
2013-2023
Florida College
1990-2015
Ophthalmology Associates (United States)
2012
University of North Texas
2012
Alfaisal University
2012
University of California, San Diego
2012
University of California, San Francisco
2012
King Khalid University Hospital
2012
King Saud University
2012
King Faisal Specialist Hospital & Research Centre
2012
Vectors derived from adeno-associated viruses (AAVs) have become important gene delivery tools for the treatment of many inherited ocular diseases in well-characterized animal models. Previous studies determined that viral capsid plays an essential role cellular tropism and efficiency transgene expression. Recently, it was shown phosphorylation surface-exposed tyrosine residues AAV2 targets particles ubiquitination proteasome- mediated degradation, mutations these lead to highly efficient...
The successful restoration of visual function with recombinant adeno-associated virus (rAAV)-mediated gene replacement therapy in animals and humans an inherited disease the retinal pigment epithelium has ushered a new era therapeutics. For many disorders, however, targeting therapeutic vectors to mutant rods and/or cones will be required. In this study, primary cone photoreceptor disorder achromatopsia served as ideal translational model develop directed photoreceptors. We demonstrate that...
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,...
Vectors based on adeno-associated virus serotype 2 (AAV2) have been used extensively in many gene-delivery applications, including several successful clinical trials for one type of Leber congenital amaurosis the retina. Many studies focused improving AAV2 transduction efficiency and cellular specificity by genetically engineering its capsid. We previously shown that vectors-containing single-point mutations capsid surface tyrosines serotypes AAV2, AAV8, AAV9 displayed significantly...
Retinal pigment epithelium-specific protein 65 kDa (RPE65) is a responsible for isomerization of all-trans-retinaldehyde to its photoactive 11-cis-retinaldehyde and essential the visual cycle. RPE65 mutations can cause severe, early onset retinal diseases such as Leber congenital amaurosis (LCA). A naturally occurring rodent model LCA with recessive nonsense Rpe65 mutation, rd12 mouse, displays profoundly diminished rod electroretinogram (ERG), an absence rhodopsin, overaccumulation retinyl...
To introduce DNA into mitochondria efficiently, we fused adenoassociated virus capsid VP2 with a mitochondrial targeting sequence to carry the gene encoding human NADH ubiquinone oxidoreductase subunit 4 (ND4). Expression of WT ND4 in cells G11778A mutation led restoration defective ATP synthesis. Furthermore, injection rodent eye, levels reached 80% its mouse homolog. The construct expressed most inner retinal neurons, and it also suppressed visual loss optic atrophy induced by mutant...
Usher syndrome 1B (USH1B) is a severe, autosomal recessive, deaf–blind disorder caused by mutations in myosin 7A (MYO7A). Patients are born profoundly deaf and exhibit progressive loss of vision starting their first decade. MYO7A expressed human photoreceptors retinal pigment epithelium, but disease pathology begins photoreceptors, highlighting the need to develop gene replacement strategy that effectively targets this cell type. For its safety efficacy clinical trials ability transduce...
Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of cone cyclic nucleotide-gated channels (CNGA3) are responsible for about 1/4 achromatopsia U.S. Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function arrest degeneration cpfl5 mouse, naturally occurring mouse model with CNGA3 mutation. We show...
Dysregulation of the complement system is implicated in neurodegeneration, including human and animal glaucoma. Optic nerve retinal damage glaucoma preceded by local upregulation activation, but whether targeting this early innate immune response could have therapeutic benefit remains undefined. Because signals through three pathways that intersect at C3 here we targeted step to restore balance glaucomatous retina determine its contribution degeneration onset and/or progression. To achieve...
IL-10 is a pluripotent cytokine that plays pivotal role in the regulation of immune and inflammatory responses. Whereas short-term administration has shown benefit acute glomerulonephritis, no studies have addressed potential benefits chronic renal disease. Chronically elevated blood levels rats were achieved by recombinant adeno-associated virus serotype 1 (rAAV1-IL-10) vector. Control given similar dose rAAV1-GFP. Four weeks after injection, serum measured ELISA, disease was induced 5/6...
Adeno-associated virus (AAV) has proven an effective gene delivery vehicle for the treatment of retinal disease. Ongoing clinical trials using a serotype 2 AAV vector to express RPE65 in pigment epithelium have safe and effective. While many proof-of-concept studies animal models disease suggested that transfer neural retina will also be effective, photoreceptor-targeting yet used clinic, principally because efficiently but exclusively targets all primate photoreceptors demonstrated. Here,...
Deficient expression of the RNase III DICER1, which leads to accumulation cytotoxic Alu RNA, has been implicated in degeneration retinal pigmented epithelium (RPE) geographic atrophy (GA), a late stage age-related macular that causes blindness millions people worldwide. Here we show increased extracellular-signal-regulated kinase (ERK) 1/2 phosphorylation RPE human eyes with GA and mouse cell culture induced by DICER1 depletion or RNA exposure is mediated via ERK1/2 signaling. overexpression...
We developed a novel strategy for treatment of Leber hereditary optic neuropathy (LHON) caused by mutation in the nicotinamide adenine dinucleotide dehydrogenase subunit IV (ND4) mitochondrial gene.OBJECTIVE To demonstrate safety and effects gene therapy vector to be used proposed clinical trial.DESIGN AND SETTING In series laboratory experiments, we modified ND4 complex I nuclear genetic code import into mitochondria.The protein was targeted organelle agency targeting sequence (allotopic...
Purpose.: The human rhodopsin (Rho) mutation T17M leads to autosomal dominant retinitis pigmentosa (adRP). goal of our study was elucidate the role endoplasmic reticulum (ER) stress in retinal degeneration hT17M Rho mice and identify potential candidates for adRP gene therapy. Methods.: We used transgenic expressing ER stress-activated indicator (ERAI) evaluate activation responses. Quantitative reverse transcription PCR (qRT-PCR) analyze changes expression 30 unfolded protein response...
Optimal phototransduction requires separation of the avascular photoreceptor layer from adjacent vascularized inner retina and choroid. Breakdown peri-photoreceptor vascular demarcation leads to retinal angiomatous proliferation or choroidal neovascularization, two variants invasion in age-related macular degeneration (AMD), leading cause irreversible blindness industrialized nations. Here we show that sFLT-1, an endogenous inhibitor endothelial growth factor A (VEGF-A), is synthesized by...
Significance One of the most common forms monogenic macular degeneration worldwide is caused by dominant or recessive bestrophinopathies associated with mutations in BEST1 gene. Disease expression known to start a retina-wide electrophysiological defect leading localized vitelliform and atrophic lesions vision loss. To develop lasting therapies for this incurable disease, there need greater understanding early pathophysiology before lesion formation. Here we find that loss retinal pigment...
Whirlin is the causative gene for Usher syndrome type IID (USH2D), a condition manifested as both retinitis pigmentosa and congenital deafness. Mutations in this cause disruption of USH2 protein complex composed USH2A VLGR1 at periciliary membrane (PMC) photoreceptors. In study, adeno-associated virus (AAV)-mediated whirlin replacement was evaluated treatment option.Murine cDNA driven by human rhodopsin kinase promoter (hRK) packaged an AAV2/5 vector delivered into knockout retina through...
Purpose.: To demonstrate safety and efficacy of allotopic human ND4 for treatment a Leber's hereditary optic neuropathy (LHON) mouse model harboring the G11778A mitochondrial mutation. Methods.: We induced LHON in mice by intravitreal injection mutant (G11778A) DNA, responsible most cases LHON, that was directed to mitochondria using an AAV2 vector which we appended targeting sequence VP2 capsid. then attempted rescue visual loss our test article (ScAAV2-P1ND4v2) containing synthetic nuclear...
Piccolo is the largest known cytomatrix protein at active zones of chemical synapses. A growing number studies on conventional synapses assign a role in recruitment and integration molecules relevant for both endo- exocytosis synaptic vesicles, dynamic assembly presynaptic F-actin, as well proteostasis proteins, yet direct function structural organization zone has not been uncovered part due to expression multiple alternatively spliced isoforms. We recently identified Piccolino, splice...
Retinitis pigmentosa (RP) is a major cause of blindness that affects 1.5 million people worldwide. Mutations in cyclic nucleotide-gated channel β 1 (CNGB1) approximately 4% autosomal recessive RP. Gene augmentation therapy shows promise for treating inherited retinal degenerations; however, relevant animal models and biomarkers progression patients with RP are needed to assess therapeutic outcomes. Here, we evaluated CNGB1 mutations potential compared human phenotypes those mouse dog the...