R.C. Andrew Symons

RNAi-Based Treatment for Neovascular Age-Related Macular Degeneration by Sirna-027

PURPOSEnTo assess the safety, tolerability, pharmacokinetics, and dose-limiting toxicity of single intravitreal injection of Sirna-027, a small interfering RNA targeting vascular endothelial growth factor receptor-1, in patients with choroidal neovascularization (CNV) resulting from neovascular age-related macular degeneration (AMD). Secondary objectives included assessment of anatomic changes in retinal thickness, size of CNV, and changes in visual acuity.nnnDESIGNnProspective, open-label, single-dose, dose-escalation phase 1 study.nnnMETHODSnTwenty-six eyes of 26 patients with a median age of 82 years and CNV resulting from AMD who had previous treatments with other therapies were treated at 2 academic retinal practices. Patients received a single dose of Sirna-027 (100, 200, 400, 800, 1200, or 1600 microg/eye). Blood was sampled for pharmacokinetic analysis at 1, 4, and 24 hours after injection and on day 7. Patients underwent ophthalmic examinations including visual acuity, fluorescein angiography, and optical coherence tomography at screening and days 7, 14, 28, and 84. The main outcome measures were adverse reactions and dose-limiting toxicities.nnnRESULTSnIntravitreal injection of a single dose of Sirna-027 from 100 to 1600 microg was well tolerated in patients with AMD, with no dose-limiting toxicity found. Adverse events were mild to moderate in severity. Adjusted mean foveal thickness decreased within 2 weeks after study treatment. The decrease was most pronounced in the 100- and 200-microg doses.nnnCONCLUSIONSnA single intravitreal dose of Sirna-027 up to 1600 microg/eye was well tolerated in patients with CNV resulting from neovascular AMD that had been refractory to other therapies. Stabilization or improvement in visual acuity and foveal thickness was observed. No dose-response or dose-limiting effects were noted.

Honokiol inhibits pathological retinal neovascularization in oxygen-induced retinopathy mouse model

Aberrant activation of the hypoxia inducible factor (HIF) pathway is the underlying cause of retinal neovascularization, one of the most common causes of blindness worldwide. The HIF pathway also plays critical roles during tumor angiogenesis and cancer stem cell transformation. We have recently shown that honokiol is a potent inhibitor of the HIF pathway in a number of cancer and retinal pigment epithelial cell lines. Here we evaluate the safety and efficacy of honokiol, digoxin, and doxorubicin, three recently identified HIF inhibitors from natural sources. Our studies show that honokiol has a better safety to efficacy profile as a HIF inhibitor than digoxin and doxorubicin. Further, we show for the first time that daily intraperitoneal injection of honokiol starting at postnatal day (P) 12 in an oxygen-induced retinopathy (OIR) mouse model significantly reduced retinal neovascularization at P17. Administration of honokiol also prevents the oxygen-induced central retinal vaso-obliteration, characteristic feature of the OIR model. Additionally, honokiol enhanced physiological revascularization of the retinal vascular plexuses. Since honokiol suppresses multiple pathways activated by HIF, in addition to the VEGF signaling, it may provide advantages over current treatments utilizing specific VEGF antagonists for ocular neovascular diseases and cancers.

Retinal disease in the C3 glomerulopathies and the risk of impaired vision

ABSTRACT Background: Dense deposit disease and atypical hemolytic uremic syndrome are often caused by Complement Factor H (CFH) mutations. This study describes the retinal abnormalities in dense deposit disease and, for the first time, atypical haemolytic uremic syndrome. It also reviews our understanding of drusen pathogenesis and their relevance for glomerular disease. Methods: Six individuals with dense deposit disease and one with atypical haemolytic uremic syndrome were studied from 2 to 40 years after presentation. Five had renal transplants. All four who had genetic testing had CFH mutations. Individuals underwent ophthalmological review and retinal photography, and in some cases, optical coherence tomography, and further tests of retinal function. Results: All subjects with dense deposit disease had impaired night vision and retinal drusen or whitish-yellow deposits. Retinal atrophy, pigmentation, and hemorrhage were common. In late disease, peripheral vision was restricted, central vision was distorted, and there were scotoma from sub-retinal choroidal neovascular membranes and atypical serous retinopathy. Drusen were present but less prominent in the young person with atypical uremic syndrome due to a heterozygous CFH mutation. Conclusions: Drusen are common in forms of C3 glomerulopathy caused by compound heterozygous or heterozygous CFH mutations. They are useful diagnostically but also impair vision. Drusen have an identical composition to glomerular deposits. They are also identical to the drusen of age-related macular degeneration, and may respond to the same treatments. Individuals with a C3 glomerulopathy should be assessed ophthalmologically at diagnosis, and monitored regularly for vision-threatening complications.

CHD7 Deficiency in “Looper”, a New Mouse Model of CHARGE Syndrome, Results in Ossicle Malformation, Otosclerosis and Hearing Impairment

CHARGE syndrome is a rare human disorder caused by mutations in the gene encoding chromodomain helicase DNA binding protein 7 (CHD7). Characteristics of CHARGE are varied and include developmental ear and hearing anomalies. Here we report a novel mouse model of CHD7 dysfunction, termed Looper. The Looper strain harbours a nonsense mutation (c.5690C>A, p.S1897X) within the Chd7 gene. Looper mice exhibit many of the clinical features of the human syndrome, consistent with previously reported CHARGE models, including growth retardation, facial asymmetry, vestibular defects, eye anomalies, hyperactivity, ossicle malformation, hearing loss and vestibular dysfunction. Looper mice display an otosclerosis-like fusion of the stapes footplate to the cochlear oval window and blepharoconjunctivitis but not coloboma. Looper mice are hyperactive and have vestibular dysfunction but do not display motor impairment.

Common ophthalmic emergencies

Ophthalmic emergencies are immediate threats to the visual system that can lead to permanent loss of visual function if left untreated. These emergencies should be detected by physicians and immediately treated and referred to an ophthalmologist if necessary. This article reviews the most common ophthalmic emergency room presentations, the history and physical examination for an ophthalmic emergency, and the diagnosis and management of each condition.

Incidence and Clinical Predictors of Ocular Candidiasis in Patients with Candida Fungemia

Purpose. The aim of this study is to determine the incidence and the predictors of ocular candidiasis among patient with Candida fungemia. Methods. We retrospectively reviewed the charts of all patients diagnosed with candidemia at the University of Kansas Medical Center during February 2000–March 2010. Data regarding patients demographics, clinical characteristics, laboratory results, and ophthalmology examination findings were collected. Results. A total of 283 patients with candidemia were enrolled. The mean age (± standard deviation) was 55 ± 18 years; 66% were male. The most commonly isolated Candida species were C. albicans (54%), C. parapsilosis (20%), C. glabrata (13%), and C. tropicalis (8%). Only 144 (51%) patients were evaluated by ophthalmology; however, the proportion of patients who were formally evaluated by an ophthalmologist increased during the study period (9%in 2000 up to 73%in 2010; P < 0.0001). Evidence of ocular candidiasis was present in 18 (12.5%) patients. Visual symptoms were reported by 5 of 18 (28%) patients. In multivariable analysis, no predictors of ocular candidiasis were identified. Conclusions. The incidence of ocular candidiasis among patients with fungemia remains elevated. Most patients are asymptomatic and therefore all patients with candidemia should undergo fundoscopic examination to rule out ocular involvement.

Bilateral Retrobulbar Optic Neuropathy in the Setting of Interferon Alpha-2a Therapy

The development of biopharmaceutical agents, including the interferons (IFN), offers new treatment options for a wide range of medical conditions. Such advancements, however, have not come without risk to patients. Optic neuropathy in the setting of IFN therapy has been previously documented and is usually attributed to anterior ischaemic optic neuropathy; however, the pathophysiology remains poorly understood. Retrobulbar optic neuropathy associated with IFN treatment has not been described in the medical literature to date. We report the case of a 38-year-old Caucasian female with refractory acute myeloid leukaemia who developed painless bilateral blurred vision within 2 weeks of commencing a course of IFN alpha-2a. Extensive clinical workup demonstrated bilateral retrobulbar optic neuropathy. We report the clinical evaluation of this first documented case and discuss the possible aetiologies of her presentation.

Cytokine Profiles in Clinical Subtypes of Ophthalmic Graves’ Disease

Abstract Purpose: To examine the association of cytokines in the two clinical subtypes of ophthalmic Graves disease by comparing cytokine expression in the fat and ethmoid tissue of type I and type II patients. Methods: Patients needing orbital decompression or eyelid surgery were identified and enrolled into a prospective study. Patients were assigned to the type I or type II subclassification, based on the presence of diplopia. Orbital fat, sinus tissue or muscle removed during surgery was evaluated. The mRNA expression profiles of Th1 cytokines (TNF-alpha/beta, IFN-gamma, IL-2) and Th2 cytokines (IL-4, IL-5, IL-6, IL-10) were analyzed using real time PCR. Results: 30 patients were enrolled in the study: 5 type I (80% female), 14 type II (71% female) and 11 controls (73% female). There were 14 decompressions (3 type I and 11 type II), 17 lid procedures (2 type I, 4 type II and 11 controls) and 10 ethmoidectomies (3 type I and 7 type II). The average ages were 45, 56 and 66 in the type I, type II and control groups, respectively. There was more TNF-alpha (p value 0.009) and IL-6 (p value 0.04) in ethmoid sinus cells of type II patients compared to ethmoid sinus cells of type I patients and a trend of higher expression of all cytokines in type II patients. Conclusions: There is a trend towards greater mRNA expression of both Th1 and Th2 cytokines in both orbital fat and ethmoidal sinus tissue of type II patients compared to type I patients.

Careful cone counting critical for clinical care.

Borrowing from modern astronomical technologies, adaptive optics (AO) offers much promise for improved ophthalmic, and particularly retinal, imaging. Its cellular-level resolution has already provided new information about the in vivo distribution of cones, retinal pigment epithelial (RPE) cells and even rod photoreceptors in health and disease, and promises new understanding of retinal capillary function and neurovascular coupling. At the heart of AO is the recently developed ability to quantify the subtle optical aberrations of the living human eye, and in real time correct these by reflecting light from precisely deformable mirrors. In the research setting, AO instruments have been available for more than a decade. Among current research instruments, there is a diversity of illumination and imaging approaches: flood (based on the optics of a standard fundus camera), confocal scanning devices (AO scanning light ophthalmoscopes) and AO-optical coherence tomography (OCT). All of these have been designed to use single or multiple wavelengths, and have various strengths and weaknesses in imaging the three-dimensional structure of the retina. Although incremental steps are being taken, commercial AO instruments have yet to become mainstream due to inherent complexities in controlling optical alignment, calibrating control loops and analysing the huge data structures delivered. The RTX-1 is the first AO device to be marketed to an audience outside of research laboratories. It is a flood-illuminated, single-wavelength device that is capable, under optimal conditions, of capturing diffraction-limited images of the smallest foveal cones. Using this device and its in-built image analysis software, Bidaut-Garnier et al. (in this issue of CEO) provide an initial characterization, in normal patients, of the variability in parafoveal cone density measurement. This exercise is an important step towards mainstream utilization of such instruments: as this report shows, obtaining high-resolution images is only the beginning. The reliability of seemingly simple analyses, such as counting cones and determining cellular densities, is influenced by inherent variations in image quality (determined by patient factors such as tear film stability, fixation and optical alignment), but also by the choices made by operators at both image acquisition and analysis stages. Users of new technology need assurance that measurements are accurate and representative of a patient’s current state of health or pathology, that results are meaningful from one day to the next, and that findings can be replicated not only by the same instrument, but also when analysing and comparing data from one imaging centre to the next. This issue’s report adds to such understanding about the confidence that one might have in any single measure of cone density, and reveals that there is more work to be done. As the presented data illustrate, an important limitation of the RTX-1 instrument is that even for normal eyes, it is not routinely capable of imaging the very central patch of foveal cones. This is demonstrated by Figs. 1c and 2 of Ref. [10], which show a decrease in the image analysis software’s report of cone density within the central 2.5°, in obvious conflict with histological findings and that of research-grade AO instruments. It would have been preferable for this central area to be removed from the cone density map in acknowledgement of the limitations of the equipment and analysis software. Nevertheless, with this caveat in mind, there is scope for useful analyses of the cone density and associated statistics to be obtained from defined regions beyond this central foveal region. Comparisons with the results of research-grade AO instruments would seem to be the next logical step. Spectral domain (SD)-OCT has become the clinical workhorse for providing high-resolution photoreceptor structural information in health and disease. For commercially available AO systems to provide a

Functional screening devices for diabetic retinopathy: Letter to the Editor

implanted with this supplementary sulcus IOL. McGrath and Lee were the first to report transscleral fixation of a supplementary toric IOL in a single pseudophakic patient. The authors externalized both IOL haptic and tied a modified cow-hitch suture to the second undulation of the haptics, close to its apex. The IOL haptic was then fixated to the sclera under a partial thickness scleral flap. The postoperative period was reported to be uneventful with refractive stability demonstrated over a 1 month period of follow-up. Our technique for stabilizing the Sulcoflex supplementary toric IOL provides a number of advantages to that reported by McGrath and Lee as it does not require externalization of the IOL haptics and requires fixation of just one haptic to provide rotational stability. Suture fixation of one haptic is beneficial in reducing the surgical time and associated tissue trauma and minimizes the potential for incorrect suture placement as previous studies have indicated that 45–70% of transscleraly fixated IOLs are located outside the sulcus on Ultrasound Biomicroscopy (UBM) examination. Although the Sulcoflex IOL is not designed with an eyelet, it has several haptic undulations which should prevent the migration of the Prolene suture and ensure long-term rotational stability. Postoperative UBM confirms the lack of IOL tilt, which is important in achieving optimal visual outcome (Fig. 3). The procedure is safe to perform, with no intraoperative or postoperative complications seen in our case series. However, suture erosion with subsequent decentration of the lens is a possibility and the long-term stability of this technique remains unknown. In summary, we present a technique of scleral fixation to stabilize a rotating supplementary toric IOL used to correct residual refractive error in pseudophakic eyes. This technique allows for safe, predictable and relatively straightforward fixation of an IOL, without requiring IOL haptic externalization. Mohammed Ziaei FRCOphth, Jay J Meyer MD MPH, Dipika V Patel PhD MRCOphth and Charles NJ McGhee DSc FRCOphth