A5008889406- Retinal Development and Disorders
- Virus-based gene therapy research
- Retinal Diseases and Treatments
- CRISPR and Genetic Engineering
- Photoreceptor and optogenetics research
- RNA Interference and Gene Delivery
- Retinal and Optic Conditions
- RNA regulation and disease
- bioluminescence and chemiluminescence research
- Herpesvirus Infections and Treatments
- Mitochondrial Function and Pathology
- Ocular Disorders and Treatments
- interferon and immune responses
- Photochromic and Fluorescence Chemistry
- Neuroscience and Neural Engineering
- Glaucoma and retinal disorders
- Connexins and lens biology
- Cytomegalovirus and herpesvirus research
- Advanced Fluorescence Microscopy Techniques
- Hearing, Cochlea, Tinnitus, Genetics
- Retinopathy of Prematurity Studies
- Advanced biosensing and bioanalysis techniques
- Photosynthetic Processes and Mechanisms
- Advanced Glycation End Products research
- Viral Infectious Diseases and Gene Expression in Insects
University of Florida
2016-2025
Florida College
2015-2024
Vector (United States)
2020
University of North Texas
2012
University of North Texas Health Science Center
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
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...
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...
Previous work established retinal expression of channelrhodopsin-2 (ChR2), an algal cation channel gated by light, restored physiological and behavioral visual responses in otherwise blind rd1 mice. However, a viable ChR2-based human therapy must meet several key criteria: (i) ChR2 be targeted, robust, long-term, (ii) provide long-term continuous therapeutic efficacy, (iii) both viral vector delivery safe. Here, we demonstrate the development clinically relevant for late stage degeneration...
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,...
Glaucoma, a major cause of blindness worldwide, is neurodegenerative optic neuropathy in which vision loss caused by retinal ganglion cells (RGCs). To better define the pathways mediating RGC death and identify targets for development neuroprotective drugs, we developed high-throughput RNA interference screen with primary RGCs used it to full mouse kinome. The identified dual leucine zipper kinase (DLK) as key target RGCs. In cultured RGCs, DLK signaling both necessary sufficient cell death....
AAV2 delivery of the RPE65 gene to retina blind RPE65-deficient animals restores vision. This strategy is being considered for human trials in RPE65-associated Leber congenital amaurosis (LCA), but toxicity and dose efficacy have not been defined. We studied ocular AAV-2/2.RPE65 RPE65-mutant dogs. There was no systemic toxicity. Ocular examinations showed mild or moderate inflammation that resolved over 3 months. Retinal histopathology indicated traumatic lesions from injection were common,...
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...
Development of viral vectors capable transducing photoreceptors by less invasive methods than subretinal injection would provide a major advancement in retinal gene therapy. We sought to develop novel AAV optimized for photoreceptor transduction following intravitreal delivery and methodology quantifying this vivo. Surface exposed tyrosine (Y) threonine (T) residues on the capsids AAV2, AAV5 AAV8 were changed phenylalanine (F) valine (V), respectively. Transduction efficiencies...
The retinal degeneration 10 (rd10) mouse is a well-characterized model of autosomal recessive retinitis pigmentosa (RP), which carries spontaneous mutation in the β subunit rod cGMP-phosphodiesterase (PDEβ). Rd10 exhibits photoreceptor dysfunction and rapid followed by cone remodeling inner retina. Here, we evaluate whether gene replacement using fast-acting tyrosine-capsid mutant AAV8 (Y733F) can provide long-term therapy this model. (Y733F)-smCBA-PDEβ was subretinally delivered to...
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...
Leber congenital amaurosis (LCA) is a molecularly heterogeneous disease group that leads to blindness. LCA caused by RPE65 mutations has been studied in animal models and vision restored subretinal delivery of AAV-RPE65 vector. Human ocular gene transfer trials are being considered. Our safety studies AAV-2/2.RPE65 RPE65-mutant dogs showed evidence modest photoreceptor loss the injection region some animals at higher vector doses. We now test hypothesis there can be vectorrelated toxicity...
purpose. To test AAV-mediated gene therapy in the rd10 mouse, a natural model of recessive RP caused by mutation β-subunit rod photoreceptor cGMP phosphodiesterase. methods. One eye cohort mice kept dark environment was subretinally injected at postnatal day (P) 14 with 1 μL AAV5-smCBA-PDEβ. The contralateral not injected. animals were then maintained for 2 weeks before they moved to normal 12-hour light/12-hour cycling light visually guided behavioral training. Three after injection,...
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,...
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...
Background Recessive mutations in guanylate cyclase-1 (Gucy2d) are associated with severe, early onset Leber congenital amaurosis-1(LCA1). Gucy2d encodes cyclase (GC1) is expressed photoreceptor outer segment membranes and produces cGMP these cells. LCA1 patients present infancy severely impaired vision extinguished electroretinogram (ERG) but retain some photoreceptors both their macular peripheral retina for years. Like patients, loss of cone function the GC1 knockout (GC1KO) mouse...