Ygal Rotenstreich

Tel Aviv University, Tell Afif, Tel Aviv, Israel

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Publications (12)40.88 Total impact

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    ABSTRACT: Vision incapacitation and blindness associated with retinal degeneration affect millions of people worldwide. Cell based therapy and specifically transplantation of human adult bone marrow-derived stem cells (hBM-MSCs) present possible treatment strategy. Subretinal transplantation of human or rat BM-MSCs was shown previously to improve retinal function in Royal College Surgeons (RCS) rats. In those studies cells were transplanted via a transscleral-transchoroidal approach, creating a localized subretinal bleb. Limited number cells could be injected and photoreceptor rescue was restricted to areas in proximity to the injection site. Here we describe a new surgical method for subretinal transplantation that facilitates uniform distribution of transplanted cells as a thin layer along most of the subretinal space. We assessed the therapeutic effect of hBM-MSCs on RCS rats when transplanted either subretinally or intravitreally. We also examined whether a second transplantation can prolong the therapeutic effect. A cell suspension of 2.5 × 10(6) cells in 5 μl was injected subretinally or intravitreally in RCS rats at 28 days postnatal. In the subretinal group, hBM-MSCs were transplanted posterior to the limbus in the superotemporal part of the eye through a longitudinal triangular scleral tunnel reaching the choroid. In the intravitreal group, the cells were injected into the superotemporal part of the vitreous cavity. In cross sections of subretinally transplanted eyes, removed 2 h following transplantation, hBM-MSCs were distributed as a near-homogenous thin layer along most of the subretinal space. In some animals the cells were also detected in the choroid. In the intravitreal injection group, hBM-MSCs were clustered in the vitreous cavity. Transplanted cells could be detected up to 2 weeks after transplantation but not at later time points. Retinal function and structure were assessed by electroretinogram (ERG) and histology analysis, respectively. Six weeks post transplantation, the mean maximal scotopic ERG b-wave amplitude response recorded in RCS control eyes was 1.2 μV. By contrast, in transplanted eyes mean responses of 56.4 μV and 66.2 μV were recorded in the intravitreally and subretinally transplanted eyes, respectively. In the subretinal group, retinal function was significantly higher in transplanted compared with control eyes up to 20 weeks following transplantation. By contrast, in the intravitreal group, rescue of retinal function persisted only up to 12 weeks following transplantation. Histological analysis revealed that 8 weeks following subretinal transplantation, the retinas of control eyes were dystrophic, with outer nuclear layer (ONL) containing a single cell layer. An extensive photoreceptor rescue was demonstrated in transplanted eyes at this time point, with 3-4 cell layers in the ONL along the entire retina. A second subretinal transplantation at 70 days postnatal did not enhance or prolong the therapeutic effect of hBM-MSCs. No immunosuppressants were used and long-term safety analysis demonstrated no gross or microscopic adverse effects. Taken together our findings suggest that transplantation of hBM-MSCs as a thin subretinal layer enhances the therapeutic effect and the safety of cell transplantation.
    Experimental Eye Research 11/2013; · 3.03 Impact Factor
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    ABSTRACT: To provide the clinical features in patients with retinal disease caused by C8orf37 gene mutations. Eight patients - four diagnosed with retinitis pigmentosa (RP) and four with cone-rod dystrophy (CRD) - carrying causal C8orf37 mutations were clinically evaluated, including extensive medical history taking, slit-lamp biomicroscopy, ophthalmoscopy, kinetic perimetry, electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), autofluorescence imaging (AF) and fundus photography. In families A and D, respectively, one and three patients showed a classic RP phenotype with night blindness followed by concentric loss of visual field. Severe visual loss to light perception occurred early in the course of the disease. The symptoms initiated during infancy (family A) or adolescence (family D). Ophthalmoscopy revealed macular atrophy, bone spicules, attenuated vessels and waxy pale optic discs. SD-OCT showed profound photoreceptor degeneration and AF demonstrated atrophy of the retinal pigment epithelium (RPE). ERG responses were non-recordable in these patients. IN FAMILIES B AND C, THE PATIENTS WERE DIAGNOSED WITH CRD. INITIAL SYMPTOMS WERE PHOTOPHOBIA OR LOSS OF VISUAL ACUITY AND OCCURRED DURING INFANCY (FAMILY B) OR ADOLESCENCE (FAMILY C). OPHTHALMOSCOPY AND AF REVEALED PROFOUND MACULAR RPE ATROPHY, SD-OCT DEMONSTRATED MACULAR PHOTORECEPTOR DEGENERATION. ERG RESPONSES WERE SEVERELY REDUCED IN A CONE-ROD PATTERN OR NON-RECORDABLE. INTERESTINGLY, BOTH PATIENTS IN FAMILY B DEMONSTRATED POLYDACTYLY. CONCLUSIONS: Mutations in C8orf37 give rise to an early or adolescent-onset arCRD or arRP phenotype with early macular atrophy. The occurrence of postaxial polydactyly in one family suggests a syndromic phenotype, which may indicate C8orf37 has a ciliary function.
    Investigative ophthalmology & visual science 06/2013; · 3.43 Impact Factor
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    ABSTRACT: IMPORTANCE Retinitis pigmentosa (RP) is the leading cause of incurable inherited blindness in the developed world, with an estimated prevalence of 1 in 3500 individuals. Therefore, it is important to develop new treatments for this disease. OBJECTIVE To determine the effect of oral treatment with 9- cis β-carotene on visual function of patients with RP. DESIGN Randomized, double-masked, placebo-controlled, crossover clinical trial. SETTING University tertiary medical facility. PARTICIPANTS Thirty-four patients with RP who were at least 18 years of age. Twenty-nine patients completed the study and were included in the analysis. INTERVENTIONS Patients were treated daily for 90 days with capsules containing 300 mg of 9- cis β-carotene-rich alga Dunaliella bardawil (β-carotene, approximately 20 mg) or placebo (starch). Following a 90-day washout period, they were treated for 90 days with the other capsules. MAIN OUTCOMES AND MEASURES The primary outcome was the change for both eyes from baseline to the end of each treatment in dark-adapted maximal electroretinographic b-wave amplitude. The secondary outcomes were the changes in light-adapted maximal b-wave amplitude, dark- and light-adapted visual field, and best-corrected visual acuity. RESULTS The mean change in dark-adapted maximal b-wave amplitude relative to initial baseline was +8.4 μV for 9- cis β-carotene vs -5.9 μV for placebo (P = .001). Ten participants (34.5%) had an increase of more than 10 μV for both eyes (range, 11-42 μV) after 9- cis β-carotene treatment compared with no participants after placebo treatment. The percentage change in light-adapted b-wave response was +17.8% for 9- cis β-carotene vs -3.0% for placebo (P = .01). No significant differences were found between the groups for visual field and best-corrected visual acuity. No adverse effects were observed. CONCLUSIONS AND RELEVANCE Treatment with 9- cis β-carotene significantly increased retinal function in patients with RP under the tested conditions. The optimal therapeutic regimen will be determined in future, larger clinical trials. 9- cis β-Carotene may represent a new therapeutic approach for some patients with RP. TRIAL REGISTRATION clinicaltrials.gov Identifier:NCT01256697.
    Jama Ophthalmology 05/2013; · 3.83 Impact Factor
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    ABSTRACT: 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 nm and 640 nm, respectively, light intensity 40 cd/m2) at thirteen different points of the 30-degree visual field (VF), under background illumination of 2.7 cd/m2. The pupillary response (PR) of patients was compared with PR obtained from normal control participants. In eleven patients, the pupillary responses were also compared with their findings on dark-adapted chromatic Goldmann. 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 non-detected in the chromatic Goldmann. 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.
    Investigative ophthalmology & visual science 03/2013; · 3.43 Impact Factor
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    ABSTRACT: Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. THE FAMILY WAS FOUND TO SEGREGATE NOVEL MUTATIONS OF TWO DIFFERENT GENES: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient.
    Molecular vision 01/2013; 19:1565-71. · 1.99 Impact Factor
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    ABSTRACT: Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb. Next-generation sequencing of all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements in these three regions revealed a homozygous nonsense mutation (c.497T>A [p.Leu166(∗)]) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single-nucleotide polymorphism databases, or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals who had retinal dystrophy and carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice-site mutation (c.156-2A>G) in two siblings of a consanguineous family and homozygous missense mutations (c.529C>T [p.Arg177Trp]; c.545A>G [p.Gln182Arg]) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are probably pathogenic. Clinical assessment revealed CRD in four individuals and RP with early macular involvement in two individuals. The two CRD siblings with the c.156-2A>G mutation also showed unilateral postaxial polydactyly. These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies.
    The American Journal of Human Genetics 12/2011; 90(1):102-9. · 11.20 Impact Factor
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    ABSTRACT: To describe the clinical findings and genetic analysis in two brothers having a novel retinal disease characterized by an enhanced S-cone phenotype with normal rod function. Both patients underwent complete ophthalmologic examinations, including fundus photography, electroretinography (ERG), fluorescein angiography and optical coherence tomography (OCT). Mutation analysis of the following candidate genes was performed: nuclear receptor subfamily 2 group E member 3 (NR2E3), neural retina leucine zipper (NRL), nuclear receptor subfamily 1 group D member 1 (NR1D1), and thyroid hormone receptor beta (THRB). Spectral photopic ERG responses demonstrated enhanced S-cone function in both patients. Their scotopic b-wave ERG amplitude responses, however, were within normal limits. Their scotopic a-wave amplitude responses were within the lower limit of normal. The a- and b-wave latencies were normal for one sibling and on the upper limit of normal for the other. Peripheral retinal findings were normal. OCT showed flattening of the macular curvature and thinning of the photoreceptor layer. Mutation analysis of NR2E3, NRL, NR1D1, and THRB genes was negative. We describe what appears to be a previously unidentified familial retinal phenotype with enhanced S-cone function and well preserved rod system function in contrast to the severely reduced rod function seen in the enhanced S-cone syndrome (ESCS). Genetic analysis of candidate genes did not reveal the cause of disease. We postulate that the disease might be caused by mutation of another, as yet unidentified gene, which encodes a protein that functions as a negative inhibitor of rod and S-cone development.
    Molecular vision 01/2011; 17:2241-7. · 1.99 Impact Factor
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    ABSTRACT: Retinal astrocytic hamartomas are benign intraocular tumors classically associated with phacomatoses. Their appearance in isolation is rare. An association between astrocytic hamartomas and retinitis pigmentosa (RP) has been described previously, but controversy still exists regarding the precise nature of these lesions in RP patients. The authors present a case report of a 24-year-old male with RP and multiple bilateral lesions clinically consistent with retinal astrocytic hamartomas. Optical coherence tomography revealed multiple bilateral hyper-reflective intraretinal masses, loss of retinal architecture, intralesional calcifications, and prominent optical posterior shadowing. Comprehensive systemic evaluation was negative for phacomatoses. However, given that a biopsy was not performed, the diagnosis of optic nerve head drusen could not be excluded.
    Clinical Ophthalmology 01/2011; 5:1663-5.
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    ABSTRACT: To assess the effect of bevacizumab (Avastin), a vascular endothelial growth factor inhibitor, on retinal function by full-field electroretinography (ERG) in patients with neovascular age-related macular degeneration (AMD). A prospective, nonrandomized, controlled interventional clinical trial. Twelve patients (aged 50)85) with neovascular AMD each received one unilateral intravitreal injection of bevacizumab 1.25 mg⁄ 0.05 ml as part of the standard management for choroidal neovascular AMD. Before and 1 month after injection, all patients underwent bilateral full-field ERG scanning by a masked technician according to the ISCEV protocol, and their wave amplitudes were recorded. Untreated eyes served as controls. Scotopic responses were recorded at four incremental light intensities and photopic responses at two incremental light intensities. Changes in ERG-amplitude responses were calculated. Repeated-measures ANOVA was used for data analysis. Mean pre- and postinjection differences in a-wave amplitudes between the incremental light intensities in injected eyes were significantly higher than in controls (15.92 versus 1.33 lV for scotopic responses and 4.97 versus )1.06 lV for photopic responses; p = 0.057 and p = 0.01, respectively). Mean b-wave amplitudes in injected eyes were significantly higher than in controls for photopic responses (p = 0.048), but for scotopic responses, the difference between treated and untreated eyes was not significant (p = 0.23). Intravitreally injected bevacizumab improves both rod and cone functioning in patients with neovascular AMD, as demonstrated by the increase in the ERG a-wave responses of these patients. Other measured ERG parameters yielded no significant photoreceptor toxicity.
    Acta ophthalmologica 10/2010; 89(3):e269-73. · 2.44 Impact Factor
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    ABSTRACT: BACKGROUND Fundus albipunctatus is a retinal dystrophy caused by a mutation in the gene encoding 11-cis-retinol dehydrogenase which delays the recovery of rod photoreceptor cells from light stimulation leading to night blindness. A recent study of a mouse model of fundus albipunctatus treated with 9-cis-retinal showed an improvement in visual function and structure. METHODS Seven patients with fundus albipunctatus were given a daily food supplement of four capsules containing high-dose 9-cis-beta-carotene for 90 days. The subjects were tested before and after treatment by visual field and electroretinogram in both eyes. This non-randomised prospective phase I study was registered at http://www.clinicaltrials.gov (NCT00478530). RESULTS All patients showed significant improvements in peripheral visual field (mean deviation improved from -4.77+/-2.0 to -3.28+/-2.28, p=0.009, t test) and a highly significant improvement in rod recovery rates measured electroretinographically (maximal scotopic b-wave amplitude responses, improved from 197+/-49 muV to 292+/-48 muV, p<0.001, t test). No complications or side effects were observed. CONCLUSION Oral treatment with 9-cis-beta-carotene led to reversal of a human retinal dystrophy. This potential therapy is readily available and should be evaluated in retinal dystrophies of similar mechanisms such as various types of retinitis pigmentosa.
    The British journal of ophthalmology 12/2009; 94(5):616-21. · 2.92 Impact Factor
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    ABSTRACT: Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations in the NBS1 gene encoding the Nbs1 (nibrin) protein. Nbs1 is a component of the Mre11/Rad50/Nbs1 (MRN) complex that acts as a sensor of double strand breaks (DSBs) in the DNA and is critical for proper activation of the broad cellular response to DSBs. Conditional disruption of the murine ortholog of the human NBS1, Nbs1, in the CNS of mice was previously reported to cause microcephaly, severe cerebellar atrophy and ataxia. Here we report that conditional targeted disruption of the murine NBS1 gene in the CNS results in mal-development, degeneration, disorganization and dysfunction of the murine visual system, especially in the optic nerve. Nbs1 deletion resulted in reduced diameters of Nbs1-CNS-Delta eye and optic nerve. MRI analysis revealed defective white matter development and organization. Nbs1 inactivation altered the morphology and organization of the glial cells. Interestingly, at the age of two-month-old the levels of the axonal guidance molecule semaphorin-3A and its receptor neuropilin-1 were up-regulated in the retina of the mutant mice, a typical injury response. Electroretinogram analysis revealed marked reduction in a- and b-waves, indicative of decreased retinal function. Our study points to a novel role for Nbs1 in the development, organization and function of the visual system.
    Experimental Neurology 05/2009; 218(1):24-32. · 4.65 Impact Factor
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    ABSTRACT: To identify the genetic cause underlying autosomal recessive cone-rod dystrophy (CORD) and high myopia. Nine members of a consanguineous Arab family were clinically examined and were given fluorescein angiography (FA), biometry, and full field electroretinogram (ERG) testing. Blood samples were collected for DNA extraction. A homozygousity genome-wide scan was performed using >382 polymorphic microsatellite markers on genomic DNA from three affected family members. Regions of homozygosity were further analyzed in all members of the family. Mutation analysis of the PROM1 gene was performed by direct sequencing of PCR-amplified exons. The phenotype is characterized by severe visual impairment evident in the first decade of life. Affected family members have bull;s-eye macular appearance, peripheral retinal pigment clumps, and cone-rod type ERG changes. Additionally, they have high myopia with axial lengths exceeding 25.3 mm. A genome-wide scan detected a region of 2.1 Mb on chromosome 4p that fully segregates with the disease within the family. This region encompasses the PROML1 gene, mutations of which have been implicated in retinal dystrophies. PROML1 mutation analysis identified a novel single nucleotide insertion at position 1629 of the cDNA resulting in truncation of approximately one-third of the protein. The mutation described in this report further expands the clinical spectrum of PROM1 mutations.
    Molecular vision 01/2009; 15:1709-16. · 1.99 Impact Factor