Ifat Sher

Epiretinal transplantation of human bone marrow mesenchymal stem cells rescues retinal and vision function in a rat model of retinal degeneration

Vision incapacitation and blindness associated with incurable retinal degeneration affect millions of people worldwide. In this study, 0.25×10(6) human bone marrow stem cells (hBM-MSCs) were transplanted epiretinally in the right eye of Royal College Surgeons (RCS) rats at the age of 28 days. Epiretinally transplanted cells were identified as a thin layer of cells along vitreous cavity, in close proximity to the retina or attached to the lens capsule, up to 6 weeks following transplantation. Epiretinal transplantation delayed photoreceptor degeneration and rescued retinal function up to 20 weeks following cell transplantation. Visual functions remained close to normal levels in epiretinal transplantation rats. No inflammation or any other adverse effects were observed in transplanted eyes. Our findings suggest that transplantation of hBM-MSCs as a thin epiretinal layer is effective for treatment of retinal degeneration in RCS rats, and that transplanting the cells in close proximity to the retina enhances hBM-MSC therapeutic effect compared with intravitreal injection.

Pupillometer-Based Objective Chromatic Perimetry in Normal Eyes and Patients With Retinal Photoreceptor Dystrophies

PURPOSE To evaluate a novel objective perimetry using multifocal chromatic pupil light reflex in normal participants and patients with photoreceptor dysfunction, and to relate this new technique with subjective dark-adapted chromatic Goldmann perimetry. METHODS Thirty-two eyes of 17 retinitis pigmentosa (RP) or cone-rod dystrophy patients and 20 eyes of 12 healthy individuals were tested. A computerized infrared video pupillometer was used to record changes in pupil diameter in response to short- and long-wavelength stimuli (peak 485 and 640 nm, respectively; light intensity 40 cd/m(2)) at 13 different points of the 30° visual field (VF), under background illumination of 2.7 cd/m(2). The pupillary response (PR) of patients was compared with PR obtained from normal control participants. In 11 patients, the pupillary responses were also compared with their findings on dark-adapted chromatic Goldmann perimetry. RESULTS Significantly reduced pupillary responses were obtained in RP patients in response to the short-wavelength stimulus in nearly all perimetric locations (P < 0.03). By contrast, in response to the long-wavelength stimulus, RP patients demonstrated significantly reduced PR mostly in peripheral locations (P ≤ 0.02). In a cone-rod dystrophy patient, the PR to both long- and short-wavelength stimuli was significantly lower in the scotoma area identified by the dark-adapted chromatic Goldmann perimetry. In all patients that were tested by the chromatic Goldmann, minimal PR was recorded in areas that were nondetected in the chromatic Goldmann perimetry. CONCLUSIONS This study demonstrates the potential feasibility of using pupillometer-based chromatic perimetry for objectively assessing VF defects and retinal function in patients with retinal dystrophies. (ClinicalTrials.gov number, NCT01021982.).

Long-Term Safety of Transplanting Human Bone Marrow Stromal Cells into the Extravascular Spaces of the Choroid of Rabbits

Incurable neuroretinal degeneration diseases cause severe vision loss and blindness in millions of patients worldwide. In previous studies, we demonstrated that transplanting human bone marrow stromal cells (hBMSCs) in the extravascular spaces of the choroid (EVSC) of the Royal College of Surgeon rats ameliorated retinal degeneration for up to 5 months. Assessing the safety of hBMSC treatment and graft survival in a large animal is a crucial step before initiating clinical trials. Here, we transplanted hBMSCs into the EVSC compartment of New Zealand White rabbits. No immunosuppressants were used. Transplanted cells were spread across the EVSC covering over 80 percent of the subretinal surface. No cells were detected in the sclera. Cells were retained in the EVSC compartment 10 weeks following transplantation. Spectral domain optical coherence tomography (SD-OCT) and histopathology analysis demonstrated no choroidal hemorrhages, retinal detachment, inflammation, or any untoward pathological reactions in any of transplanted eyes or in the control noninjected contralateral eyes. No reduction in retinal function was recorded by electroretinogram up to 10 weeks following transplantation. This study demonstrates the feasibility and safety of transplanting hBMSCs in the EVSC compartment in a large eye model of rabbits.

A minimally invasive adjustable‐depth blunt injector for delivery of pharmaceuticals into the posterior pole

To investigate the feasibility and safety of a novel minimally invasive adjustable‐depth blunt injector for pharmaceuticals delivery into the posterior segment.

The first prototype of chromatic pupillometer for objective perimetry in retinal degeneration patients

We recently demonstrated the feasibility of quantifying pupil responses (PR) to multifocal chromatic light stimuli for objectively assessing visual field (VF). Here we assessed a second-generation chromatic multifocal pupillometer device with 76 LEDs of 18 degree visual field and a smaller spot size (2mm diameter), aimed of achieving better perimetric resolution. A computerized infrared pupillometer was used to record PR to short- and long-wavelength stimuli (peak 485 nm and 640 nm, respectively) presented by 76 LEDs, 1.8mm spot size, at light intensities of 10-1000 cd/m2 at different points of the 18 degree VF. PR amplitude was measured in 11 retinitis pigmentosa (RP) patients and 20 normal agedmatched controls. RP patients demonstrated statistically significant reduced pupil contraction amplitude in majority of perimetric locations under testing conditions that emphasized rod contribution (short-wavelength stimuli at 200 cd/m2) in peripheral locations (p<0.05). By contrast, the amplitude of pupillary responses under testing conditions that emphasized cone cell contribution (long-wavelength stimuli at 1000 cd/m2) were not significantly different between the groups in majority of perimetric locations, particularly in central locations. Minimal pupil contraction was recorded in areas that were non-detected by chromatic Goldmann. This study demonstrates the feasibility of using pupillometerbased chromatic perimetry for objectively assessing VF defects and retinal function in patients with retinal degeneration. This method may be used to distinguish between the damaged cells underlying the VF defect.

Synthetic 9- cis -beta-carotene inhibits photoreceptor degeneration in cultures of eye cups from rpe65rd12 mouse model of retinoid cycle defect

The retinoid cycle enzymes regenerate the visual chromophore 11-cis retinal to enable vision. Mutations in the genes encoding the proteins of the retinoid cycle are the leading cause for recessively inherited retinal dystrophies such as retinitis pigmentosa, Leber congenital amaurosis, congenital cone-rod dystrophy and fundus albipunctatus. Currently there is no treatment for these blinding diseases. In previous studies we demonstrated that oral treatment with the 9-cis-β-carotene rich Dunaliella Bardawil algae powder significantly improved visual and retinal functions in patients with retinitis pigmentosa and fundus albipunctatus. Here we developed a convenient and economical synthetic route for biologically active 9-cis-β-carotene from inexpensive building materials and demonstrated that the molecule is stable for at least one month. Synthetic 9-cis-β-carotene rescued cone photoreceptors from degeneration in eye cup cultures of mice with a retinoid cycle genetic defect. This study suggests that synthetic 9-cis-β-carotene may serve as an effective treatment for retinal dystrophies involving the retinoid cycle.

ASSOCIATION OF STRUCTURAL RETINAL MARKERS WITH BRAIN STRUCTURE IN ASYMPTOMATIC INDIVIDUALS AT HIGH RISK FOR ALZHEIMER’S DISEASE

P3-217 ASSOCIATIONOF STRUCTURALRETINAL MARKERS WITH BRAIN STRUCTURE IN ASYMPTOMATIC INDIVIDUALS AT HIGH RISK FOR ALZHEIMER’S DISEASE Inbal Sharvit-Ginon, Michal Schnaider Beeri, Abigail Livny, Aron Weller, Ifat Sher, Ygal Rotenstreich, Ramit Ravona-Springer, Bar Ilan University, Ramat Gan, Israel; Sheba Medical Center, Ramat Gan, Israel; Department of Diagnostic Imaging and The Joseph Sagol Neuroscience Center, Sheba Medical Center, Ramat-Gan, Israel; Tel Aviv University, Tel Aviv, Israel. Contact e-mail: Ramit.Ravona@sheba.health. gov.il

ASSOCIATION OF STRUCTURAL RETINAL MARKERS WITH COGNITIVE FUNCTION IN ASYMPTOMATIC INDIVIDUALS AT HIGH RISK FOR ALZHEIMER'S DISEASE

Odile Habert, Christian Neri, Bruno Dubois, Simone Lista and INSIGHT-preAD Study group for the Alzheimer Precision Medicine Initiative, Sorbonne Universit e, Assistance Publique – Hôpitaux de Paris, Alzheimer Precision Medicine, Hôpital de la Piti e-Salpêtri ere, Paris, France; Institut du Cerveau et de la Moelle Epini ere, INSERM, Centre National de la Recherche Scientifique, Paris, France; Institut de la M emoire et de laMaladie d’Alzheimer, D epartement de Neurologie, Hôpital de la Piti e-Salpêtri ere, Assistance Publique – Hôpitaux de Paris, Paris, France; AXA Research Fund and Sorbonne Universit e, Paris, France; Institut de Biologie Paris-Seine, Centre National de la Recherche Scientifique, Biological Adaptation and Ageing, Sorbonne Universit e, Paris, France; ADx NeuroSciences NV, Technologiepark, Gent, Belgium; Assistance Publique – Hôpitaux de Paris, UF Biochimie des Maladies Neuro-m etaboliques, Service de Biochimie M etabolique, Groupe Hospitalier Piti e-Salpêtri ere, Paris, France; Istituto di Ricovero e Cura a Carattere Scientifico, Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Centre pour l’Acquisition et le Traitement des Images, Paris, France; Assistance Publique – Hôpitaux de Paris, Hôpital Piti e-Salpêtri ere, D epartement de M edecine Nucl eaire, Paris, France; Sorbonne Universit es, University Pierre and Marie Curie, Centre National de la Recherche Scientifique, INSERM, Laboratoire d’Imagerie Biom edicale, Paris, France. Contact e-mail: harald.hampel@icm-institute.org

Chromatic multifocal pupillometer for objective early diagnosis of mild cognitive impairment

The pupil responses of 15 cognitively normal subjects (ages 60-74) were examined in response to 76 focal red and blue light stimuli using a chromatic multifocal pupillometer (CMP). Subjects with low cognitive scores as determined as by Montreal Cognitive Assessment testing, presented significantly weaker and sluggish pupil responses in peripheral and central locations of the visual field in response to red and blue light. Our findings suggests that the CMP may present a novel objective, non-invasive, low cost technique for early diagnosis of cognitive decline that may serve for Alzheimer Disease prevention and as sensitive outcome measure of therapeutic effects.

Chromatic multifocal pupillometry for objective perimetry in patients with Best's vitelliform macular dystrophy (Conference Presentation)

Purpose: Objective pupilloperimetry in healthy subjects and patients with Best’s Vitelliform Macular Dystrophy using a chromatic multifocal pupillometer (CMP). Methods: A CMP (Accutome Inc) was used to record pupillary responses (PR) of 17 healthy subjects and 5 Best’s patients. Red and blue light stimuli were presented at 76 locations of a 16.2 degree VF. The PR of patients were compared with their findings on Humphreys 24-2 perimetry, Optical Coherence Tomography (OCT) and with the PR of healthy subjects. Percentage of Pupil Constriction (PPC), maximal constriction velocity (MCV) and the latency of MCV (LMCV) were determined. Results: In response to red light, Best’s patients demonstrated reduced PPC and slower MCV compared with healthy subjects in nearly all test point locations. Severity of defects in PPC in responses to red light correlated with reduced thickness of photoreceptor layer as determined by OCT in the central, superior, nasal and temporal areas of the central retina (Pearsons r= -0.93, -0.91, -0.92, -0.85, respectively). By contrast, in response to blue light stimuli, the PPC and MCV of patients were lower than normal only in several central points. Surprisingly, the latency of MCV was shorter in patients compared with healthy subjects in response to red and blue stimuli. Conclusions: This study demonstrates the potential feasibility of using pupillometer-based chromatic perimetry for objectively assessing VF defects in patients with Best’s macular dystrophy. Our findings also suggest that chromatic pupilloperimetry may differentiate between PR mediated by cones or rods, and can specifically detect defects in macular cones.