This laboratory is titled Translational Research, as we use inherited retinal degenerations identified in the clinic as both a source of clues about retinal function and dysfunction and a target for research in therapeutic intervention. Current efforts focus on human X-linked juvenile retinoschisis (XLRS). XLRS is an inherited disease and is a leading cause of juvenile macular degeneration in human males. It is due to mutations in the retinoschisin (RS) gene found on the X chromosome. We are working to understand the disease mechanisms that bring about retinal structural changes and neuronal synaptic signaling deficiency in a mouse model created in this laboratory section. At the same time, we are developing gene transfer therapy using a viral vector to supply a normal copy of the retinoschisin gene to the retina of patients in which it is defective. . Our current understanding is based on a study of human affected patients and on analysis of the XLRS mouse model. We have probed the biochemistry and sub-cellular localization of the retinoschisin protein and have localized it to particular cell membrane sites of photoreceptors and synapses and measured changes in key membrane proteins in synapses. We discovered molecular interactions between retinoschisin and photoreceptor membrane phospholipids biochemically and with atomic force microscopy that may explain its role in neuronal structure and retinal signaling. We cloned and characterized the human gene promoter region and have identified the key regulatory sites. We characterized the biochemical consequences of certain human mutations in the RS gene, and showed that they lead to an absence of the protein. Detailed study of long-term disease progression in the XLRS mouse revealed significant correlations between degenerative structural changes and functional neuronal signaling abnormalities. Such studies currently are not possible in human and provide us better understanding of disease mechanisms and give clues on designing appropriate endpoint metrics for eventual human clinical trial. We showed retinal rescue of structure and function in the XLRS mouse by viral (AAV) vector retinoschisin gene transfer, and we are now characterizing appropriate intervention times in disease progression, doses and other parameters that lead to success or failure of gene transfer. We are also disigning and preparing a human AAV- retinoschisin gene transfer experiment. Clinical protocol: Clinical and Genetic Studies of X-Linked Juvenile Retinoschisis Identifier: NCT00055029 The objectives of this registry are to understand the nature of the XLRS disease in order to develop appropriate treatments by characterizing the anatomical and functional characteristics of retinoschisis and ultimately generate a well-documented genotype-phenotype correlation map. A minimum of 100 males diagnosed with X-linked retinoschisis will undergo clinical examination and have their blood drawn for genotyping. Blood will also be drawn from available and consenting mothers of affected males. An eye examination will be performed and blood drawn from any symptomatic available and consenting female family members. A maximum of 500 affected males and family members may be enrolled. Sites outside of NIH are participating as referral centers to accumulate the cohort.

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National Institute on Deafness and Other Communication Disorders
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Marangoni, Dario; Yong, Zeng; Kjellström, Sten et al. (2017) Rearing Light Intensity Affects Inner Retinal Pathology in a Mouse Model of X-Linked Retinoschisis but Does Not Alter Gene Therapy Outcome. Invest Ophthalmol Vis Sci 58:1656-1664
Marangoni, Dario; Bush, Ronald A; Zeng, Yong et al. (2016) Ocular and systemic safety of a recombinant AAV8 vector for X-linked retinoschisis gene therapy: GLP studies in rabbits and Rs1-KO mice. Mol Ther Methods Clin Dev 5:16011
Zeng, Yong; Petralia, Ronald S; Vijayasarathy, Camasamudram et al. (2016) Retinal Structure and Gene Therapy Outcome in Retinoschisin-Deficient Mice Assessed by Spectral-Domain Optical Coherence Tomography. Invest Ophthalmol Vis Sci 57:OCT277-87
Tolun, Gökhan; Vijayasarathy, Camasamudram; Huang, Rick et al. (2016) Paired octamer rings of retinoschisin suggest a junctional model for cell-cell adhesion in the retina. Proc Natl Acad Sci U S A 113:5287-92
Bush, Ronald A; Zeng, Yong; Colosi, Peter et al. (2016) Preclinical Dose-Escalation Study of Intravitreal AAV-RS1 Gene Therapy in a Mouse Model of X-linked Retinoschisis: Dose-Dependent Expression and Improved Retinal Structure and Function. Hum Gene Ther 27:376-89
Bush, Ronald A; Wei, Lisa L; Sieving, Paul A (2015) Convergence of Human Genetics and Animal Studies: Gene Therapy for X-Linked Retinoschisis. Cold Spring Harb Perspect Med 5:
Ou, Jingxing; Vijayasarathy, Camasamudram; Ziccardi, Lucia et al. (2015) Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer. J Clin Invest 125:2891-903
Ziccardi, Lucia; Vijayasarathy, Camasamudram; Bush, Ronald A et al. (2014) Photoreceptor pathology in the X-linked retinoschisis (XLRS) mouse results in delayed rod maturation and impaired light driven transducin translocation. Adv Exp Med Biol 801:559-66
Marangoni, Dario; Wu, Zhijian; Wiley, Henry E et al. (2014) Preclinical Safety Evaluation of a Recombinant AAV8 Vector for X-linked Retinoschisis after Intravitreal Administration in Rabbits. Hum Gene Ther Clin Dev :
Jeffrey, Brett G; Cukras, Catherine A; Vitale, Susan et al. (2014) Test-Retest Intervisit Variability of Functional and Structural Parameters in X-Linked Retinoschisis. Transl Vis Sci Technol 3:5

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