Komáromy, András M

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  • Publication
    Application of a New Subretinal Injection Device in the Dog
    (2006-06-01) Komáromy, András M; Varner, Signe E; de Juan, Eugene; Acland, Gregory M; Aguirre, Gustavo D
    The use of a new subretinal injection device (RetinaJect™ Subretinal Cannula, SurModics, Inc., Eden Prairie, MN) to access the subretinal space in the canine model was evaluated. Subretinal injections were performed in 33 mongrel dogs between 2 and 52 months of age (median = 9 months). In 5 normal dogs the injection of 150 μl saline or India ink occurred by using a conventional subretinal injection device (CSID) with a 30-gauge anterior chamber irrigating cannula. The sclera had to be surgically exposed and penetrated before the subretinal injection with the CSID could occur. After removing the CSID, the conjunctiva over the sclerotomy site had to be closed. In a second group of 28 dogs [16 normals, 10 RPE65 mutants, and 2 with progressive rod cone degeneration (prcd)], the 25-gauge needle of the RetinaJect™ was used to penetrate the conjunctiva and the sclera. Once the tip of the needle was close to the retinal surface, a 39-gauge polyimide cannula was extended and brought into apposition with the retina for the subsequent subretinal injection of 150 μl saline, India ink, or adeno-associated virus (AAV). No closure of the conjunctiva was required. The animals were clinically monitored between 1 and 59 weeks after surgery. From this second group 25 eyes were harvested for routine histological analysis either immediately after surgery or after a clinical observation time of between 1 and 40 weeks. Both devices provided equally successful access to the subretinal space. The main advantage of the RetinaJect™ was that no surgical dissection was required; this led to a shorter procedure time and milder postoperative conjunctival swelling. In summary, the use of the RetinaJect™ can be recommended as an alternative to the CSID for subretinal injections in dogs.
  • Publication
    Recombinant AAV-Mediated BEST1 Transfer to the Retinal Pigment Epithelium: Analysis of Serotype-Dependent Retinal Effects
    (2013-10-15) Guziewicz, Karina E; Zangerl, Barbara; Komáromy, András M; Beltran, William; Iwabe, Simone; Chiodo, Vincent A; Boye, Sanford L; Hauswirth, William W
    Mutations in the BEST1 gene constitute an underlying cause of juvenile macular dystrophies, a group of retinal disorders commonly referred to as bestrophinopathies and usually diagnosed in early childhood or adolescence. The disease primarily affects macular and paramacular regions of the eye leading to major declines in central vision later in life. Currently, there is no cure or surgical management for BEST1-associated disorders. The recently characterized human disease counterpart, canine multifocal retinopathy (cmr), recapitulates a full spectrum of clinical and molecular features observed in human bestrophinopathies and offers a valuable model system for development and testing of therapeutic strategies. In this study, the specificity, efficiency and safety of rAAV-mediated transgene expression driven by the human VMD2 promoter were assessed in wild-type canine retinae. While the subretinal delivery of rAAV2/1 vector serotype was associated with cone damage in the retina when BEST1 and GFP were co-expressed, the rAAV2/2 vector serotype carrying either GFP reporter or BEST1 transgene under control of human VMD2 promoter was safe, and enabled specific transduction of the RPE cell monolayer that was stable for up to 6 months post injection. These encouraging studies with the rAAV2/2 vector lay the groundwork for development of gene augmentation therapy for human bestrophinopathies.
  • Publication
    Primary Adenocarcinoma of the Gland of the Nictitating Membrane in a Cat
    (1997-07-01) Komáromy, András M; Ramsey, David T; Render, James A; Clark, Phillip
    An 11-year-old, neutered, male domestic shorthair was presented with a five-month history of recurrent, unilateral, seromucoid discharge from the right eye. A verrucous mass extended from the posterior aspect of the nictitating membrane. Adenocarcinoma of the gland of the nictitating membrand (GNM) was diagnosed upon biopsy. The cat subsequently developed metastases to the lungs, pleura, mediastinum, liver, and kidneys and died six months after clinical signs first were observed. Little is known about the biological behavior of adenocarcinoma of the GNM in cats. This is the first report that describes the natural progression of this disease.
  • Publication
    BEST1 Gene Therapy Corrects a Diffuse Retina-Wide Microdetachment Modulated by Light Exposure
    (2018-03-20) Guziewicz, Karina E; Cideciyan, Artur V; Beltran, William A; Komáromy, András M; Ruthel, Gordon; Dufour, Valerie L; Swider, Malgorzata; Iwabe, Simone; Jacobson, Samuel G; Sumaroka, Alexander; Kendrick, Brian T; Chiodo, Vince A; Heon, Elise; Hauswirth, William W
    Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE-PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE-PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE-PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies.
  • Publication
    Targeting Gene Expression to Cones With Human Cone Opsin Promoters in Recombinant AAV
    (2008-07-01) Komáromy, András M; Aguirre, Gustavo D; Alexander, John J; Cooper, Anne E; Chodo, Vince A; Acland, Gregory M; Hauswirth, William W
    Specific cone-directed therapy is of high priority in the treatment of human hereditary retinal diseases. However, not much information exists about the specific targeting of photoreceptor subclasses. Three versions of the human red cone opsin promoter (PR0.5, 3LCR-PR0.5 and PR2.1), and the human blue cone opsin promoter HB569, were evaluated for their specificity and robustness in targeting green fluorescent protein (GFP) gene expression to subclasses of cones in the canine retina when used in recombinant adeno-associated viral vectors of serotype 5. The vectors were administered by subretinal injection. The promoter PR2.1 led to most effective and specific expression of GFP in the long- and medium-wavelength-absorbing cones (L/M cones) of normal and diseased retinas. The PR0.5 promoter was not effective. Adding three copies of the 35-bp LCR in front of PR0.5 lead to weak GFP expression in L/M cones. The HB569 promoter was not specific, and GFP was expressed in a few L/M cones, some rods and the retinal pigment epithelium. These results suggest that L/M cones, the predominant class of cone photoreceptors in the retinas of dogs and most mammalian species can be successfully targeted using the human red cone opsin promoter.
  • Publication
    Operating in the Dark: A Night-Vision System for Surgery in Retinas Susceptible to Light Damage
    (2008-05-01) Komáromy, András M; Aguirre, Gustavo D; Acland, Gregory M
    A standard operating microscope was modified with a bandpass infrared filter in the light path and infrared image intensifiers for each of the 2 eyepieces. We evaluated this system for subretinal injections in normal control dogs and those with a mutation in the rhodopsin gene. Rhodopsin-mutant dogs are a model for human autosomal dominant retinitis pigmentosa, and their retinas degenerate faster when exposed to modest light levels as used in routine clinical examinations. We showed that the mutant retinas developed severe generalized degeneration when exposed to the standard operating microscope light but not the infrared light. The modified operating microscope provided an excellent view of the ocular fundus under infrared illumination and allowed us to perform subretinal injections in the retinas of the rhodopsin-mutant dogs without any subsequent light-induced retinal degeneration. The first description of light-induced retinal damage showed that exposure of albino rats to visible light intensities ordinarily encountered in the laboratory led to irreversible retinal damage.1 This finding soon was extended to other species, including rabbits2 and monkeys.3 Studies in animal models of retinal degeneration (eg, Royal College of Surgeons rats, ABCA4-mutant mice, or rhodopsin-mutant mice and dogs) have emphasized the interplay between the gene mutation and environmental light and demonstrated acceleration of the disease process by light.4- 10 The effect of environmental light on disease severity in humans with retinitis pigmentosa has been suggested by case reports,11 although definitive proof is lacking. However, patients with class B1 rhodopsin mutations may be at risk of accelerated vision loss with increased light exposures because they have defects in dark (bleaching) adaptation similar to those found in rhodopsin-mutant dogs that demonstrate a high susceptibility to retinal light damage.8,12,13 Many of the emerging therapies for retinal degeneration require the intraocular placement of a reagent or device with the use of an operating microscope.14,15 The damaging effect of the microscope light on the normal retina, even with the appropriate filtering of UV light, has been described previously,16,17 and there is increased emphasis on reducing the intensity and duration of the exposures. Herein, we describe a modification of an operating microscope with an infrared bandpass filter and a night-vision system to perform surgical interventions in the posterior segment of the eyes of rhodopsin-mutant dogs without the risk of photochemical retinal damage. This modification prevents acceleration of the photoreceptor degeneration that occurs with exposure to modest light levels as used in routine clinical practice.8 If humans with retinitis pigmentosa are shown to have similar light damage susceptibility, this microscope modification could be considered for surgical procedures such as the subretinal application of gene therapy vectors.
  • Publication
    Intraocular Nematodiasis in a Llama (Lama glama)
    (2011-02-01) Sweeney, Raymond W; Habecker, Perry L; Dunkel, Bettina; Komáromy, András M
    This report describes a unique case of presumed migration of Parelaphastrongylus tenuis through the spinal cord into the eye of a llama where it survived and matured within the ocular environment. Blindness of the eye was most likely attributable to migration of the parasite through the central nervous tissue. Résumé Infestation par les nématodes intraoculaire chez un lama (Lama glama). Ce rapport décrit un cas unique de migration présumée de Parelaphastrongylus tenuis dans la colonne vertébrale jusque dans l’œil d’un lama où il a survécu et est parvenu à maturité dans l’environnement oculaire. La cécité de l’œil a été le plus probablement attribuable à la migration du parasite dans les tissus du système nerveux central. (Traduit par Isabelle Vallières)
  • Publication
    Transient Photoreceptor Deconstruction by CNTF Enhances rAAV-Mediated Cone Functional Rescue in Late Stage CNGB3-Achromatopsia
    (2013-06-01) Komáromy, András M; Aguirre, Gustavo D; Rowlan, Jessica S; Parton Corr, Amanda T; Reinstein, Shelby L; Boye, Sanford L; Cooper, Ann E; Gonzalez, Amaliris; Levy, Britt; Beltran, William A; Wen, Rong; Hauswirth, William W
    Achromatopsia is a genetic disorder of cones, and one of the most common forms is a channelopathy caused by mutations in the β-subunit, CNGB3, of the cone cyclic nucleotide-gated (CNG) channel. Recombinant adeno-associated virus of serotype 5 (rAAV5)-mediated gene transfer of human CNGB3 cDNA to mutant dog cones results in functional and structural rescue in dogs <0.5 years of age, but treatment is minimally effective in dogs >1 year. We now test a new therapeutic concept by combining gene therapy with the administration of ciliary neurotrophic factor (CNTF). Intravitreal CNTF causes transient dedifferentiation of photoreceptors, a process called deconstruction, whereby visual cells become immature with short outer segments, and decreased retinal function and gene expression that subsequently return to normal. Cone function was successfully rescued in all mutant dogs treated between 14 and 42 months of age with this strategy. CNTF-mediated deconstruction and regeneration of the photoreceptor outer segments prepares the mutant cones optimally for gene augmentation therapy.
  • Publication
    Safety in Nonhuman Primates of Ocular AAV2-RPE65, a Candidate Treatment for Blindness in Leber Congenital Amaurosis
    (2006-08-01) Jacobson, Samuel G; Aguirre, Gustavo D; Aleman, Tomas S; Cideciyan, Artur V; Boye, Sanford L; Komáromy, András M; Conlon, Thomas J; Zeiss, Caroline J; Roman, Alejandro J; Schwartz, Sharon B; Maguire, Albert M; Doobrajh, Michelle; Cheung, Andy Y; Sumaroka, Alexandar; Pearce-Kelling, Susan E; Kaushal, Shalesh; Flotte, Terence R; Hauswirth, William W
    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 injections of AAV-2/2. RPE65 in normal cynomolgus monkeys were performed for 1-week and 3-month durations. Systemic toxicity was not identified. Ocular-specific studies included clinical examinations, electroretinography, and retinal histopathology. Signs of ocular inflammation postinjection had almost disappeared by 1 week. At 3 months, electroretinography in vector-injected eyes was no different than in vehicle-injected control eyes or compared with presurgical recordings. Healed sites of retinal perforation from subretinal injections were noted clinically and by histopathology. Foveal architecture in subretinally injected eyes, vector or vehicle, could be abnormal. Morphometry of central retina showed no photoreceptor layer thickness abnormalities occurring in a dose-dependent manner. Vector sequences were present in the injected retina, vitreous, and optic nerve at 1 week but not consistently in the brain. At 3 months, there were no vector sequences in optic nerve and brain. The results allow for consideration of an upper range for no observed adverse effect level in future human trials of subretinal AAV-2/2. RPE65. The potential value of foveal treatment for LCA and other retinal degenerations warrants further research into how to achieve gene transfer without retinal injury from surgical detachment of the retina.
  • Publication
    Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation
    (2007-06-26) Aguirre, Geoffrey K; Komáromy, András M; Cideciyan, Artur V; Brainard, David H; Aleman, Tomas S; Avants, Brian B; Gee, James C; Jacobson, Samuel G; Roman, Alejandro J; Korczykowski, Marc; Hauswirth, William W; Acland, Gregory M
    Background RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to RPE65 mutations (RPE65-LCA). Methods and Findings RPE65-mutant dogs were studied with fMRI. Prior to therapy, retinal and subcortical responses to light were markedly diminished, and there were minimal cortical responses within the primary visual areas of the lateral gyrus (activation amplitude mean ± standard deviation [SD] = 0.07% ± 0.06% and volume = 1.3 ± 0.6 cm3). Following therapy, retinal and subcortical response restoration was accompanied by increased amplitude (0.18% ± 0.06%) and volume (8.2 ± 0.8 cm3) of activation within the lateral gyrus (p < 0.005 for both). Cortical recovery occurred rapidly (within a month of treatment) and was persistent (as long as 2.5 y after treatment). Recovery was present even when treatment was provided as late as 1–4 y of age. Human RPE65-LCA patients (ages 18–23 y) were studied with structural magnetic resonance imaging. Optic nerve diameter (3.2 ± 0.5 mm) was within the normal range (3.2 ± 0.3 mm), and occipital cortical white matter density as judged by voxel-based morphometry was slightly but significantly altered (1.3 SD below control average, p = 0.005). Functional magnetic resonance imaging in human RPE65-LCA patients revealed cortical responses with a markedly diminished activation volume (8.8 ± 1.2 cm3) compared to controls (29.7 ± 8.3 cm3, p < 0.001) when stimulated with lower intensity light. Unexpectedly, cortical response volume (41.2 ± 11.1 cm3) was comparable to normal (48.8 ± 3.1 cm3, p = 0.2) with higher intensity light stimulation. Conclusions Visual cortical responses dramatically improve after retinal gene therapy in the canine model of RPE65-LCA. Human RPE65-LCA patients have preserved visual pathway anatomy and detectable cortical activation despite limited visual experience. Taken together, the results support the potential for human visual benefit from retinal therapies currently being aimed at restoring vision to the congenitally blind with genetic retinal disease.