Medicine and Health Sciences Commons^™

Raav2/5 Gene-Targeting To Rods: Dose-Dependent Efficiency And Complications Associated With Different Promoters, William Beltran, Sanford L. Boye, Shannon E. Boye, Vince A. Chiodo, Alfred S. Lewin, William W. Hauswirth, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

A prerequisite for using corrective gene therapy to treat humans with inherited retinal degenerative diseases that primarily affect rods is to develop viral vectors that target specifically this population of photoreceptors. The delivery of a viral vector with photoreceptor tropism coupled with a rod-specific promoter is likely to be the safest and most efficient approach to target expression of the therapeutic gene to rods. Three promoters that included a fragment of the proximal mouse opsin promoter (mOP), the human G-protein-coupled receptor protein kinase 1 promoter (hGRK1), or the cytomegalovirus immediate early enhancer combined with the chicken β actin proximal promoter …

Safety In Nonhuman Primates Of Ocular Aav2-Rpe65, A Candidate Treatment For Blindness In Leber Congenital Amaurosis, Samuel G. Jacobson, Sanford L. Boye, Tomas S. Aleman, Thomas J. Conlon, Caroline J. Zeiss, Alejandro J. Roman, Artur V. Cideciyan, Sharon B. Schwartz, András M. Komáromy, Michelle Doobrajh, Andy Y. Cheung, Alexandar Sumaroka, Susan E. Pearce-Kelling, Gustavo D. Aguirre, Shalesh Kaushal, Albert M. Maguire, Terence R. Flotte, William W. Hauswirth

Gustavo D. Aguirre, VMD, PhD

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 has been restored by subretinal delivery of AAV- RPE65 vector. Human ocular gene transfer trials are being considered. Our safety studies of subretinal AAV-2/2. RPE65 in RPE65 -mutant dogs showed evidence of modest photoreceptor loss in the injection region in some animals at higher vector doses. We now test the hypothesis that there can be vector-related toxicity to the normal monkey, with its human-like retina. Good Laboratory Practice safety studies following single intraocular …

Photoreceptor Cell Death, Proliferation And Formation Of Hybrid Rod/S-Cone Photoreceptors In The Degenerating Stk38l Mutant Retina, Ágnes I. Berta, Kathleen Boesze-Battaglia, Sem Genini, Orly Goldstein, Paul J. O'Brien, Ágoston Szél, Gregory M. Acland, William Beltran, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

A homozygous mutation in STK38L in dogs impairs the late phase of photoreceptor development, and is followed by photoreceptor cell death (TUNEL) and proliferation (PCNA, PHH3) events that occur independently in different cells between 7–14 weeks of age. During this period, the outer nuclear layer (ONL) cell number is unchanged. The dividing cells are of photoreceptor origin, have rod opsin labeling, and do not label with markers specific for macrophages/microglia (CD18) or Müller cells (glutamine synthetase, PAX6). Nestin labeling is absent from the ONL although it labels the peripheral retina and ciliary marginal zone equally in normals and mutants. Cell …

Canine Retina Has A Primate Fovea-Like Bouquet Of Cone Photoreceptors Which Is Affected By Inherited Macular Degenerations, William Beltran, Artur V. Cideciyan, Karina E. Guziewicz, Simone Iwabe, Erin M. Scott, Svetlana V. Savina, Gordon Ruthel, Frank Stefano, Lingli Zhang, Richard Zorger, Alexander Sumaroka, Samuel G. Jacobson, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

Retinal areas of specialization confer vertebrates with the ability to scrutinize corresponding regions of their visual field with greater resolution. A highly specialized area found in haplorhine primates (including humans) is the fovea centralis which is defined by a high density of cone photoreceptors connected individually to interneurons, and retinal ganglion cells (RGCs) that are offset to form a pit lacking retinal capillaries and inner retinal neurons at its center. In dogs, a local increase in RGC density is found in a topographically comparable retinal area defined as the area centralis. While the canine retina is devoid of a foveal …

A Kutya Mint Modell Az Örökletes Retinadegenerációk Kutatásában / The Dog As A Model In Research Into Inherited Retinal Degenerations, Ágnes I. Berta, Ágoston Szél, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

Összefoglalás: A kutya mint modellállat csak az elmúlt 15 évben került az érdeklődés középpontjába. A kutya retinája különösen érdekes, mivel számos örökletes retinadegeneráció szoros homológiát mutat az ember hasonló betegségeivel. Röviden összefoglaljuk a kutya retinájának sajátosságait és azokat az alapkutatásban használt módszereket, melyek segítségével a retina degenerációja leírható kutyában. A kutya örökletes retinadegenerációi közül a szemészek számára a legérdekesebb csoport a progresszív retinalis atrophia (PRA), mivel genetikai, patológiai és klinikai szempontból is nagyon hasonló a retinitis pigmentosa különböző típusaihoz. A PRA csoport tagjai élő modellrendszerek, melyek alkalmazhatók az örökletes retinadegenerációk alap- és klinikai kutatásában egyaránt. Ezekben a súlyos és mindenekelőtt …

Cloning And Characterization Of The Cdna Encoding The Α-Subunit Of Cgmp-Phosphodiesterase In Canine Retinal Rod Photoreceptor Cells, Weiquan Wang, Gregory M. Acland, Gustavo D. Aguirre, Kunal Ray

Gustavo D. Aguirre, VMD, PhD

No abstract provided.

Up-Regulation Of Tumor Necrosis Factor Superfamily Genes In Early Phases Of Photoreceptor Degeneration, Sem Genini, William Beltran, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

We used quantitative real-time PCR to examine the expression of 112 genes related to retinal function and/or belonging to known pro-apoptotic, cell survival, and autophagy pathways during photoreceptor degeneration in three early-onset canine models of human photoreceptor degeneration, rod cone dysplasia 1 (rcd1), X-linked progressive retinal atrophy 2 (xlpra2), and early retinal degeneration (erd), caused respectively, by mutations in PDE6B, RPGRORF15, and STK38L. Notably, we found that expression and timing of differentially expressed (DE) genes correlated with the cell death kinetics. Gene expression profiles of rcd1 and xlpra2 were similar; however rcd1 was more severe as demonstrated by the results …

Intravitreal Injection Of Ciliary Neurotrophic Factor (Cntf) Causes Peripheral Remodeling And Does Not Prevent Photoreceptor Loss In Canine Rpgr Mutant Retina, William Beltran, Rong Wen, Gregory M. Acland, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

Ciliary neurotrophic factor (CNTF) rescues photoreceptors in several animal models of retinal degeneration and is currently being evaluated as a potential treatment for retinitis pigmentosa in humans. This study was conducted to test whether CNTF prevents photoreceptor cell loss in XLPRA2, an early onset canine model of X-linked retinitis pigmentosa caused by a frameshift mutation in RPGR exon ORF15. Four different treatment regimens of CNTF were tested in XLPRA2 dogs. Under anesthesia, the animals received at different ages an intravitreal injection of 12 μg of CNTF in the left eye. The right eye served as a control and was injected …

Two Forms Of The Large Tumor Suppressor Gene (Lats1) Protein Expressed In The Vertebrate Retina, Novrouz B. Akhmedov, Clyde K. Yamashita, Dai Tran, Natik I. Piri, Gustavo D. Aguirre, Debora B. Farber

Gustavo D. Aguirre, VMD, PhD

Comparative Analysis, Gene Organization And Expression Of Canine Tcte1l, Kui Li, Qi Zhang, Jennifer L. Johnson, Gustavo D. Aguirre

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

Selective Absence Of Cone Outer Segment Β3-Transducin Immunoreactivity In Hereditary Cone Degeneration (Cd), Kathryn Gropp, A. Széll, Jun Huang, Gregory Acland, Debora Farber, Gustavo Aguirre

Gustavo D. Aguirre, VMD, PhD

Interphotoreceptor Retinoid-Binding Protein (Irbp) In Progressive Rod-Cone Degeneration (Prcd)—Biochemical, Immunocytochemical And Immunologic Studies, Gustavo Aguirre, Barbara Wiggert, Geetha Kutty, Kenneth Long, Lila Inouye, Igal Gery, Gerald Chader

Gustavo D. Aguirre, VMD, PhD

The Cone Matrix Sheath In The Normal And Diseased Retina: Cytochemical And Biochemical Studies Of Peanut Agglutinin-Binding Proteins In Cone And Rod-Cone Degeneration, Kenneth Long, Gustavo Aguirre

Gustavo D. Aguirre, VMD, PhD

Β-Glucuronidase Mediated Pathway Essential For Retinal Pigment Epithelial Degradation Of Glycosaminoglycans. Disease Expression And In Vitro Disease Correction Using Retroviral Mediated Cdna Transfer, Lawrence Stramm, John Wolfe, Edward Schuchman, Mark Haskins, Donald Patterson, Gustavo Aguirre

Gustavo D. Aguirre, VMD, PhD