Medicine and Health Sciences Commons^™

Durable Vision Improvement After A Single Intravitreal Treatment With Antisense Oligonucleotide In Cep290-Lca: Replication In Two Eyes, Artur V Cideciyan, Samuel G Jacobson, Allen Ho, Malgorzata Swider, Alexander Sumaroka, Alejandro J Roman, Vivian Wu, Robert C Russell, Iryna Viarbitskaya, Alexandra V Garafalo, Michael R Schwartz, Aniz Girach

Wills Eye Hospital Papers

PURPOSE: An intravitreally injected antisense oligonucleotide, sepofarsen, was designed to modulate splicing within retinas of patients with severe vision loss due to deep intronic c.2991 + 1655A > G variant in the

OBSERVATIONS: Visual function was evaluated with best corrected standard and low-luminance visual acuities, microperimetry, dark-adapted chromatic perimetry, and full-field sensitivity testing. Retinal structure was evaluated with OCT imaging. At the fovea, all visual function measures and IS/OS intensity of the OCT showed transient improvements peaking at 3-6 months, remaining better than baseline at ∼2 years, and returning to baseline by 3-4 years after each single injection.

CONCLUSIONS AND IMPORTANCE: …

Neuropeptide Y Overexpression In The Presence Of P23h Rhodopsin Mutation, Jean Sun

All ETDs from UAB

Neuropeptide Y (NPY), a 36-amino acid peptide, has been found to be the most abundant neuropeptide in the central nervous system, and it is widespread across mammalian species. NPY plays a dual role as a neurotransmitter and neuromodulator in the nervous system. NPY functions as a multifaceted neuromodulator through binding NPY receptors (NPYRs). NYP interacts with NPYRs and regulates various activities, such as cell growth, neurogenesis, neuroprotection, mitochondrial behaviors, food intake, anxiety, and addiction formation. In terms of NPY’s neuroprotective potential, NPY inhibits neuronal death signaling, thus preventing apoptosis, and displays anti-inflammatory and anti-oxidative effects. Additionally, it influences metabolism by …

Anti-Retinal Igg Antibodies In Patients With Early And Advanced Type 2 Macular Telangiectasia, Samuel Mclenachan, Chandrakumar Balaratnasingam, Rachael C. Heath Jeffery, Shang Chih Chen, Dan Zhang, Geoffrey Chan, Rosa Dolz-Marco, Tommaso Bacci, Johnny Lo, Steven Wiffen, Lawrence A. Yannuzzi, Fred K. Chen

Research outputs 2022 to 2026

Type 2 idiopathic macular telangiectasia (MacTel-2) is a progressive adult-onset macular disease associated with bilateral perifoveal vascular changes, Muller cell degeneration and increased blood-retinal barrier permeability. The pathophysiological mechanisms of MacTel-2 remain unclear, however it was previously reported that anti-retinal antibodies in MacTel-2 patients are a significant feature of the disease. In this study, we aimed to compare the prevalence of anti-retinal antibodies in patients MacTel-2, healthy controls and patients with other retinal diseases. MacTel-2 patients diagnosed with multimodal imaging were enrolled and their disease severities were graded using spectral-domain optical coherence tomography. For comparison, patients with age-related macular degeneration …

Nutrigenetic Reprogramming Of Oxidative Stress, Joseph Ryu, Huzeifa Gulamhusein, Jin Kyun Oh, Joseph H. Chang, Jocelyn Chen, Stephen H. Tsang

School of Medicine Publications and Presentations

Retinal disorders such as retinitis pigmentosa, age-related retinal degeneration, oxygen-induced retinopathy, and ischemia-reperfusion injury cause debilitating and irreversible vision loss. While the exact mechanisms underlying these conditions remain unclear, there has been a growing body of evidence demonstrating the pathological contributions of oxidative stress across different cell types within the eye. Nuclear factor erythroid-2-related factor (Nrf2), a transcriptional activator of antioxidative genes, and its regulator Kelch-like ECH-associated protein 1 (Keap1) have emerged as promising therapeutic targets. The purpose of this review is to understand the protective role of the Nrf2-Keap1 pathway in different retinal tissues and shed light on the …

From Inner Segment To Outer Segment: Palmitoylation Of Photoreceptor Na+, K+-Atpase And The Importance Of Prcd In Photoreceptor Outer Segment Morphogenesis, Emily R. Sechrest

Graduate Theses, Dissertations, and Problem Reports

Photoreceptors are specialized neuroepithelial cells which are optimized for efficient capture of light and initiation of visual transduction. These cells have several compartments which are very important for proper visual function and segregation of cellular processes, including the outer segment (OS), inner segment (IS), nucleus, and synapse. The IS houses all of the cellular organelles and biosynthetic molecular machinery the cell requires and is the site of protein synthesis. The light-sensing OS is a highly modified, primary cilium, which contains many stacks of double membranous discs which house proteins required for formation and maintenance of OS structure, as well as …

Modulation Of Inflammatory Pathway By Inflammatory Inhibitor Jsh-23 Mitigates Diabetic Retinopathy., Rubens Petit Homme

Electronic Theses and Dissertations

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM). Its pathology is consisted of the breakdown of the blood-retinal barrier (BRB), particularly the inner blood-retinal barrier (iBRB). The exact mechanism that leads to the iBRB impairment and the development of DR has not been elucidated yet. However, chronic inflammation that is hallmark of the type I DM has recently become a key focus in DR study. Hyperglycemia causes dysregulation of nuclear factor-kappa B (NF-kB); and its constant activation increases the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and intercellular adhesion molecule-1 (ICAM-1) in the …

A Novel Mutation In The Choroideremia Gene In A Turkish Family., Mustafa Iftikhar, Yulia Wolfson, Simrat Sodhi, Bushra Usmani, Hendrik P. N. Scholl, Syed M.A. Shah

Medical College Documents

Choroideremia is an X-linked recessive genetic disorder caused by mutations in the CHM gene. It is a rare retinal dystrophy that manifests as nyctalopia and vision loss, progressing to blindness in later stages. We report a 21-year Turkish man who presented with nyctalopia for the past 4-5 years. His mother and maternal grandmother had similar, but less pronounced complaints. Fundus examination revealed pigmentary changes and retinal atrophy in both eyes. Optical coherence tomography showed outer retinal loss, with central island of preserved autofluorescence surrounded by absent autofluorescence on fundus autofluorescence examination. Goldmann visual fields were constricted. Microperimetry detected retinal sensitivity …

Is Retinal Metabolic Dysfunction At The Center Of The Pathogenesis Of Age-Related Macular Degeneration?, Thierry Léveillard, Nancy J. Philp, Florian Sennlaub

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The retinal pigment epithelium (RPE) forms the outer blood⁻retina barrier and facilitates the transepithelial transport of glucose into the outer retina via GLUT1. Glucose is metabolized in photoreceptors via the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS) but also by aerobic glycolysis to generate glycerol for the synthesis of phospholipids for the renewal of their outer segments. Aerobic glycolysis in the photoreceptors also leads to a high rate of production of lactate which is transported out of the subretinal space to the choroidal circulation by the RPE. Lactate taken up by the RPE is converted to pyruvate and metabolized …

The Role Of Protein Synthesis Attenuation And Eif2-Alpha Phosphorylation In Retinal Degeneration, Christopher Ryan Starr

All ETDs from UAB

Inherited retinal degeneration is a class of diseases in which there is no cure and very few treatment options available. An activated unfolded protein response has been detected in various animal models of retinal degenerative diseases. Several groups have found heightened activation of one pathway of the unfolded protein response in particular, the protein kinase R-like endoplasmic reticulum kinase signaling cascade, which converges on and phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 to transiently halt protein synthesis and allow the cell to reestablish homeostasis. Although it is widely accepted that this signaling is inherently protective, hyperactivity or …

Exonic Sine Insertion In Stk38l Causes Canine Early Retinal Degeneration (Erd), Orly Goldstein, Anna V. Kukekova, Gustavo D. Aguirre, Gregory M. Acland

Gustavo D. Aguirre, VMD, PhD

Fine mapping followed by candidate gene analysis of erd — a canine hereditary retinal degeneration characterized by aberrant photoreceptor development — established that the disease cosegregates with a SINE insertion in exon 4 of the canine STK38L/NDR2 gene. The mutation removes exon 4 from STK38L transcripts and is predicted to remove much of the N terminus from the translated protein, including binding sites for S100B and Mob proteins, part of the protein kinase domain, and a Thr-75 residue critical for autophosphorylation. Although known to have roles in neuronal cell function, the STK38L pathway has not previously been implicated in normal …

Identical Mutation In A Novel Retinal Gene Causes Progressive Rod-Cone Degeneration In Dogs And Retinitis Pigmentosa In Humans, Barbara Zangerl, Orly Goldstein, Alisdair R. Philip, Sarah J. P Lindauer, Susan E. Pearce-Kelling, Roberts F. Mullins, Alexander S. Graphodatsky, Daniel Ripoll, Jeanette S. Felix, Edwin M. Stone, Gregory M. Acland, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

Progressive rod–cone degeneration (prcd) is a late-onset, autosomal recessive photoreceptor degeneration of dogs and a homolog for some forms of human retinitis pigmentosa (RP). Previously, the disease-relevant interval was reduced to a 106-kb region on CFA9, and a common phenotype-specific haplotype was identified in all affected dogs from several different breeds and breed varieties. Screening of a canine retinal EST library identified partial cDNAs for novel candidate genes in the disease-relevant interval. The complete cDNA of one of these, PRCD, was cloned in dog, human, and mouse. The gene codes for a 54-amino-acid (aa) protein in dog and human and …

Canine Rd3 Mutation Establishes Rod-Cone Dysplasia Type 2 (Rcd2) As Ortholog Of Human And Murine Rd3, Anna V. Kukekova, Orly Goldstein, Jennifer L. Johnson, Malcolm A. Richardson, Susan E. Pearce-Kelling, Anand Swaroop, James S. Friedman, Gustavo D. Aguirre, Gregory M. Acland

Gustavo D. Aguirre, VMD, PhD

Rod-cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed and to fine map rcd2 to a 230-kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2 and is predicted to alter the last 61 codons of the normal open reading frame and further extend …

Col9a2 And Col9a3 Mutations In Canine Autosomal Recessive Oculoskeletal Dysplasia, Orly Goldstein, Richard Guyon, Anna Kukekova, Tatyana N. Kuznetsova, Susan E. Pearce-Kelling, Jennifer Johnson, Gustavo D. Aguirre, Gregory M. Acland

Gustavo D. Aguirre, VMD, PhD

Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the …

Linkage Disequilibrium Mapping In Domestic Dog Breeds Narrows The Progressive Rod-Cone Degeneration Interval And Identifies Ancestral Disease-Transmitting Chromosome, Orly Goldstein, Barbara Zangerl, Sue Pearce-Kelling, Duska J. Sidjanin, James W. Kijas, Jeanette Felix, Gregory M. Acland, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

Canine progressive rod–cone degeneration (prcd) is a retinal disease previously mapped to a broad, gene-rich centromeric region of canine chromosome 9. As allelic disorders are present in multiple breeds, we used linkage disequilibrium (LD) to narrow the ∼6.4-Mb interval candidate region. Multiple dog breeds, each representing genetically isolated populations, were typed for SNPs and other polymorphisms identified from BACs. The candidate region was initially localized to a 1.5-Mb zero recombination interval between growth factor receptor-bound protein 2 (GRB2) and SEC14-like 1 (SEC14L). A fine-scale haplotype of the region was developed, which reduced the LD interval to 106 kb and identified …

Long-Term Restoration Of Rod And Cone Vision By Single Dose Raav-Mediated Gene Transfer To The Retina In A Canine Model Of Childhood Blindness, Gregory M. Acland, Gustavo D. Aguirre, Jean Bennett, Tomas S. Aleman, Artur V. Cideciyan, Jeannette Bennicelli, Nadine S. Dejneka, Susan E. Pearce-Kelling, Albert M. Maguire, Krzysztof Palczewski, William W. Hauswirth, Samuel G. Jacobson

Gustavo D. Aguirre, VMD, PhD

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 RPE65 deficiency. Results with AAV 2/2, 2/1, and 2/5 vector pseudotypes, human or canine RPE65 cDNA, and constitutive or tissue-specific promoters were similar. Subretinally administered vectors restored retinal function in 23 of 26 eyes, but intravitreal injections consistently did not. Photoreceptoral and postreceptoral function in both rod and cone systems improved with therapy. In dogs followed electroretinographically for 3 years, responses remained stable. Biochemical analysis of retinal retinoids indicates that mutant dogs have no …

Genetic And Phenotypic Variations Of Inherited Retinal Diseases In Dogs: The Power Of Within- And Across-Breed Studies, Keiko Miyadera, Gregory M. Acland, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than …

The Unfolded Protein Response And Calcium Dysregulation In Autosomal Dominant Retinitis Pigmentosa Animal Models., Vishal Madhukar Shinde

All ETDs from UAB

The photoreceptor cell death in autosomal dominant retinitis pigmentosa (ADRP) is associated with molecular changes that occur due to mutations in a specific gene. S334ter RHO and P23H RHO are two ADRP rat models expressing mutant rhodopsin. The unfolded protein response (UPR) is a cellular stress response involved in the pathophysiology of several retinal disorders including P23H RHO rats. Considering our previous findings, we started our investigation by examining the status of UPR in S334ter RHO rats. As UPR tightly regulates several signaling pathways, we further studied whether UPR activation in S334ter and P23H RHO retina is accompanied by the …

Vascular Disrupting Agent For Neovascular Age Related Macular Degeneration: A Pilot Study Of The Safety And Efficacy Of Intravenous Combretastatin A-4 Phosphate, Mohamed A. Ibrahim, Diana V. Do, Yasir J. Sepah, Syed M. Shah, Elizabeth Van Anden, Gulnar Hafiz, J. Kevin Donahue, Richard Rivers, Jai Balkissoon, James T. Handa, Peter A. Campochiaro, Quan Dong Nguyen

Journal Articles: Ophthalmology

BACKGROUND:

This study was designed to assess the safety, tolerability, and efficacy of intravenous infusion of CA4P in patients with neovascular age-related macular degeneration (AMD).

METHODS:

Prospective, interventional, dose-escalation clinical trial. Eight patients with neovascular AMD refractory to at least 2 sessions of photodynamic therapy received CA4P at a dose of 27 or 36 mg/m2 as weekly intravenous infusion for 4 consecutive weeks. Safety was monitored by vital signs, ocular and physical examinations, electrocardiogram, routine laboratory tests, and collection of adverse events. Efficacy was assessed using retinal fluorescein angiography, optical coherence tomography, and best corrected visual acuity (BCVA).

RESULTS:

The …

Rhodopsin Trafficking And Retinal Function, Nicholas Joseph Reish

All ETDs from UAB

The health and maintenance of rod photoreceptors depends on the high-fidelity vectorial transport of rhodopsin from its site of synthesis in the inner segment to its final resting place in the outer segment disks. Multiple molecular interactions play a role in this process, including the interaction of the small GTPase rab11a with rhodopsin that was first described in vertebrates in amphibians. We found that the interaction of the small GTPase rab11a and rhodopsin is conserved in mammalian retina. This interaction is direct, is abrogated by human disease-causing truncation mutations in rhodopsin, and does not depend on the nucleotide binding status …

Protection Of Retinal Cells From Ischemia By A Novel Gap Junction Inhibitor, Satyabrata Das, Dingo Lin, Snehalata Jena, Aibin Shi, Srinivas Battina, Duy H. Hua, Rachel A. Allbaugh, Dolores J. Takemoto

Rachel A. Allbaugh

Retinal cells which become ischemic will pass apoptotic signal to adjacent cells, resulting in the spread of damage. This occurs through open gap junctions. A class of novel drugs, based on primaquine (PQ), was tested for binding to connexin 43 using simulated docking studies. A novel drug has been synthesized and tested for inhibition of gap junction activity using R28 neuro-retinal cells in culture. Four drugs were initially compared to mefloquine, a known gap junction inhibitor. The drug with optimal inhibitory activity, PQ1, was tested for inhibition and was found to inhibit dye transfer by 70% at 10 μM. Retinal …

Cannabinoids: A Novel Treatment Strategy For Retinal Neurodegenerative Disorders, Sandeep Samudre

Theses and Dissertations in Biomedical Sciences

Synthetic and naturally occurring cannabinoids are known to decrease intraocular pressure (IOP). Glaucomatous damage to the retina and optic nerve progresses even after therapy to maintain normal intraocular pressure (IOP). Topical application of cannabinoids decreases IOP while not affecting blood pressure or heart rate. Based upon their effects on other tissues, we hypothesize that these analogs reduce IOP and may also confer direct neuroprotective effects on the retina, possibly via CB1 and/or CB2 receptors. The purpose of this study is to determine if the newly synthesized CB agonists, lipid soluble O-1812 (CB 1), and water soluble O-2545 (CB 1

The …

Retinal Degeneration Due To Enrofloxacin Intoxication In A Cat, Murat Şaroğlu, Di̇lek Olgun Erdi̇kmen

Turkish Journal of Veterinary & Animal Sciences

In this case presentation, retinal degeneration due to enrofloxacin intoxication encountered in a domestic short-haired male cat is discussed. History of the patient revealed that he had received 7.8 mg/kg enrofloxacin twice daily for 10 days. Both pupils were dilated. Pupillary light reflexes were negative in both eyes. Direct and indirect ophthalmoscopic examinations showed tapetal hyperreflectivity, and slight attenuation of the retinal blood vessels compared to those of a healthy cat was observed in both retinas. Follow-up information obtained from the owner by telephone 6, 12, and 18 months later revealed that there had been no improvement in the cat´s …

Retinal Histopathology Of An Xlrp Carrier With A Mutation In The Rpgr Exon Orf15, Gustavo Aguirre, Beverly Yashar, Sinoj John, Julie Smith, K Breuer, S Hiriyanna, Anand Swaroop, Ann Milam

Gustavo D. Aguirre, VMD, PhD

Molecular Cloning, Characterization And Expression Of A Novel Retinal Clusterin-Like Protein Cdna, Qi Zhang, Kunal Ray, Gregory M. Acland, Jill M. Czarnecki, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

Timp-1 Expression Is Increased In X-Linked Progressive Retinal Atrophy Despite Its Exclusion As A Candidate Gene, Caroline Zeiss, Gregory M. Acland, Gustavo D. Aguirre, Kunal Ray

Gustavo D. Aguirre, VMD, PhD

Characterization Of Canine Photoreceptor Phosducin Cdna And Identification Of A Sequence Variant In Dogs With Photoreceptor Dysplasia, Qi Zhang, Gregory M. Acland, Charles J. Parhsall, Jeanette Haskell, Kunal Ray, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

Canine Rod Photoreceptor Cgmp-Gated Channel Protein Α-Subunit: Studies On The Expression Of The Gene And Characterization Of The Cdna, Qi Zhang, Sue Pearce-Kelling, Gregory Acland, Gustavo Aguirre, Kunal Ray

Gustavo D. Aguirre, VMD, PhD

Differential Expression Of Photoreceptor-Specific Proteins During Disease And Degeneration In The Progressive Rod-Cone Degeneration (Prcd) Retina, Kathryn Gropp, Jun Huang, Gustavo Aguirre

Gustavo D. Aguirre, VMD, PhD

An Improved Diagnostic Test For Rod Cone Dysplasia 1 (Rcdl) Using Allele-Specific Polymerase Chain Reaction, Kunal Ray, Maria Lara Tejero, Victoria Baldwin, Gustavo Aguirre

Gustavo D. Aguirre, VMD, PhD

Plasma Lipid Changes In Prcd-Affected And Normal Miniature Poodles Given Oral Supplements Of Linseed Oil. Indications For The Involvement Of N-3 Fatty Acids In Inherited Retinal Degenerations, Robert E. Anderson, Maureen B. Maude, Gregory M. Acland, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD