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Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse

Gene Therapy volume 16, pages 916–926 (2009)Cite this article

A Corrigendum to this article was published on 09 July 2009

Abstract

X-linked juvenile retinoschisis (XLRS) is a neurodevelopmental abnormality caused by retinoschisin gene mutations. XLRS is characterized by splitting through the retinal layers and impaired synaptic transmission of visual signals resulting in impaired acuity and a propensity to retinal detachment. Several groups have treated murine retinoschisis models successfully using adeno-associated virus (AAV) vectors. Owing to the fragile nature of XLRS retina, translating this therapy to the clinic may require an alternative to invasive subretinal vector administration. Here we show that all layers of the retinoschisin knockout (Rs1-KO) mouse retina can be transduced efficiently with AAV vectors administered by simple vitreous injection. Retinoschisin expression was restricted to the neuroretina using a new vector that uses a 3.5-kb human retinoschisin promoter and an AAV type 8 capsid. Intravitreal administration to Rs1-KO mice resulted in robust retinoschisin expression with a retinal distribution similar to that observed in wild-type retina, including the expression by the photoreceptors lying deep in the retina. No off-target expression was observed. Rs1-KO mice treated with this vector showed a decrease in the schisis cavities and had improved retinal signaling evaluated by recording the electroretinogram 11–15 weeks after the application.

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References

  1. Sikkink SK, Biswas S, Parry NR, Stanga PE, Trump D . X-linked retinoschisis: an update. J Med Genet 2007; 44: 225–232.

    Article  CAS  Google Scholar 

  2. Tantri A, Vrabec TR, Cu-Unjieng A, Frost A, Annesley Jr WH, Donoso LA . X-linked retinoschisis: a clinical and molecular genetic review. Surv Ophthalmol 2004; 49: 214–230.

    Article  Google Scholar 

  3. Prenner JL, Capone Jr A, Ciaccia S, Takada Y, Sieving PA, Trese MT . Congenital X-linked retinoschisis classification system. Retina 2006; 26 (7 Suppl): S61–S64.

    Article  Google Scholar 

  4. Minami Y, Ishiko S, Takai Y, Kato Y, Kagokawa H, Takamiya A et al. Retinal changes in juvenile X linked retinoschisis using three dimensional optical coherence tomography. Br J Ophthalmol 2005; 89: 1663–1664.

    Article  CAS  Google Scholar 

  5. Peachey NS, Fishman GA, Derlacki DJ, Brigell MG . Psychophysical and electroretinographic findings in X-linked juvenile retinoschisis. Arch Ophthalmol 1987; 105: 513–516.

    Article  CAS  Google Scholar 

  6. George ND, Yates JR, Moore AT . X linked retinoschisis. Br J Ophthalmol 1995; 79: 697–702.

    Article  CAS  Google Scholar 

  7. Roesch MT, Ewing CC, Gibson AE, Weber BH . The natural history of X-linked retinoschisis. Can J Ophthalmol 1998; 33: 149–158.

    CAS  PubMed  Google Scholar 

  8. Sasaki K, Ideta H, Yonemoto J, Tanaka S, Hirose A, Oka C . Epidemiologic characterstics of rhegmatogenous retinal detachement in Kumamoto, Japan. Graefes Arch Clin Exp Ophthalmol 1995; 233: 772–776.

    Article  CAS  Google Scholar 

  9. Kellner U, Brümmer S, Foerster MH, Wessing A . X-linked congenital retinoschisis. Graefes Arch Clin Exp Ophthalmol 1990; 228: 432–437.

    Article  CAS  Google Scholar 

  10. Regillo CD, Tasman WS, Brown GC . Surgical management of complications associated with X-linked retinoschisis. Arch Ophthalmol 1993; 111: 1080–1086.

    Article  CAS  Google Scholar 

  11. Rosenfeld PJ, Flynn Jr HW, McDonald HR, Rubsamen PE, Smiddy WE, Sipperley JO et al. Outcomes of vitreoretinal surgery in patients with X-linked retinoschisis. Ophthalmic Surg Lasers 1998; 29: 190–197.

    CAS  PubMed  Google Scholar 

  12. Sauer CG, Gehrig A, Warneke-Wittstock R, Marquardt A, Ewing CC, Gibson A et al. Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nat Genet 1997; 17: 164–170.

    Article  CAS  Google Scholar 

  13. Takada Y, Fariss RN, Muller M, Bush RA, Rushing EJ, Sieving PA . Retinoschisin expression and localization in rodent and human pineal and consequences of mouse RS1 gene knockout. Mol Vis 2006; 12: 1108–1116.

    CAS  PubMed  Google Scholar 

  14. Baumgartner S, Hofmann K, Chiquet-Ehrismann R, Bucher P . The discoidin domain family revisited: new members from prokaryotes and a homology-based fold prediction. Protein Sci 1998; 7: 1626–1631.

    Article  CAS  Google Scholar 

  15. Wu WW, Wong JP, Kast J, Molday RS . RS1, a discoidin domain-containing retinal cell adhesion protein associated with X-linked retinoschisis, exists as a novel disulfide-linked octamer. J Biol Chem 2005; 280: 10721–10730.

    Article  CAS  Google Scholar 

  16. Steiner-Champliaud MF, Sahel J, Hicks D . Retinoschisin forms a multi-molecular complex with extracellular matrix and cytoplasmic proteins: interactions with beta2 laminin and alphaB-crystallin. Mol Vis 2006; 12: 892–901.

    CAS  PubMed  Google Scholar 

  17. Vijayasarathy C, Takada Y, Zeng Y, Bush RA, Sieving PA . Retinoschisin is a peripheral membrane protein with affinity for anionic phospholipids and affected by divalent cations. Invest Ophthalmol Vis Sci 2007; 48: 991–1000.

    Article  Google Scholar 

  18. Molday LL, Wu WW, Molday RS . Retinoschisin (RS1), the protein encoded by the X-linked retinoschisis gene, is anchored to the surface of retinal photoreceptor and bipolar cells through its interactions with a Na/K ATPase-SARM1 complex. J Biol Chem 2007; 282: 32792–32801.

    Article  CAS  Google Scholar 

  19. Dyka FM, Wu WW, Pfeifer TA, Molday LL, Grigliatti TA, Molday RS . Characterization and purification of the discoidin domain-containing protein retinoschisin and its interaction with galactose. Biochemistry 2008; 47: 9098–9106.

    Article  CAS  Google Scholar 

  20. Takada Y, Fariss RN, Tanikawa A, Zeng Y, Carper D, Bush R et al. A retinal neuronal developmental wave of retinoschisin expression begins in ganglion cells during layer formation. Invest Ophthalmol Vis Sci 2004; 45: 3302–3312.

    Article  Google Scholar 

  21. Zeng Y, Takada Y, Kjellstrom S, Hiriyanna K, Tanikawa A, Wawrousek E et al. RS-1 gene delivery to an adult Rs1h knockout mouse model restores ERG b-wave with reversal of the electronegative waveform of X-linked retinoschisis. Invest Ophthalmol Vis Sci 2004; 45: 3279–3285.

    Article  Google Scholar 

  22. Min SH, Molday LL, Seeliger MW, Dinculescu A, Timmers AM, Janssen A et al. Prolonged recovery of retinal structure/function after gene therapy in an Rs1h-deficient mouse model of x-linked juvenile retinoschisis. Mol Ther 2005; 12: 644–651.

    Article  CAS  Google Scholar 

  23. Maguire AM, Simonelli F, Pierce EA, Pugh Jr EN, Mingozzi F, Bennicelli J et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med 2008; 358: 2240–2248.

    Article  CAS  Google Scholar 

  24. Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med 2008; 358: 2231–2239.

    Article  CAS  Google Scholar 

  25. Cideciyan AV, Aleman TS, Boye SL, Schwartz SB, Kaushal S, Roman AJ et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA 2008; 105: 15112–15117.

    Article  CAS  Google Scholar 

  26. Lebherz C, Maguire A, Tang W, Bennett J, Wilson JM . Novel AAV serotypes for improved ocular gene transfer. J Gene Med 2008; 10: 375–382.

    Article  CAS  Google Scholar 

  27. Natkunarajah M, Trittibach P, McIntosh J, Duran Y, Barker SE, Smith AJ et al. Assessment of ocular transduction using single-stranded and self-complementary recombinant adeno-associated virus serotype 2/8. Gene Therapy 2008; 15: 463–467.

    Article  CAS  Google Scholar 

  28. Takada Y, Vijayasarathy C, Zeng Y, Kjellstrom S, Bush RA, Sieving PA . Synaptic pathology in retinoschisis knockout (Rs1−/y) mouse retina and modification by rAAV-Rs1 gene delivery. Invest Ophthalmol Vis Sci 2008; 49: 3677–3686.

    Article  Google Scholar 

  29. Kjellstrom S, Bush RA, Zeng Y, Takada Y, Sieving PA . Retinoschisin gene therapy and natural history in the Rs1h-KO mouse: long-term rescue from retinal degeneration. Invest Ophthalmol Vis Sci 2007; 48: 3837–3845.

    Article  Google Scholar 

  30. Bradshaw K, George N, Moore A, Trump D . Mutations of the XLRS1 gene cause abnormalities of photoreceptor as well as inner retinal responses of the ERG. Doc Ophthalmol 1999; 98: 153–173.

    Article  CAS  Google Scholar 

  31. Sieving PA, Bingham EL, Kemp L, Richards J, Hiriyanna K . Juvenile X-linked retinoschisis from XLRS1 Arg213Trp mutation with preservation of the electroretinogram scotopic b-wave. Am J Ophthalmol 1999; 128: 179–184.

    Article  CAS  Google Scholar 

  32. Xie Q, Bu W, Bhatia S, Hare J, Somasundaram T, Azzi A et al. The atomic structure of adeno-associated virus (AAV-2), a vector for human gene therapy. Proc Natl Acad Sci USA 2002; 99: 10405–10410.

    Article  CAS  Google Scholar 

  33. Walters RW, Agbandje-McKenna M, Bowman VD, Moninger TO, Olson NH, Seiler M et al. Structure of adeno-associated virus serotype 5. J Virol 2004; 78: 3361–3371.

    Article  CAS  Google Scholar 

  34. Nam HJ, Lane MD, Padron E, Gurda B, McKenna R, Kohlbrenner E et al. Structure of adeno-associated virus serotype 8, a gene therapy vector. J Virol 2007; 81: 12260–12271.

    Article  CAS  Google Scholar 

  35. Gonzalez-Fernandez F . Interphotoreceptor retinoid-binding protein: an old gene for new eyes. Vision Res 2003; 43: 3021–3036.

    Article  CAS  Google Scholar 

  36. Grimm D, Zhou S, Nakai H, Thomas CE, Storm TA, Fuess S et al. Preclinical in vivo evaluation of pseudotyped adeno-associated virus vectors for liver gene therapy. Blood 2003; 102: 2412–2419.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Maria Santos for help with husbandry and Jinbo Li for help with histology.

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Authors and Affiliations

  1. Section for translational Research in Retinal and Macular Degeneration (STRRMD), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), Bethesda, MD, USA

    T K Park, S Kjellstrom, Y Zeng, R A Bush & P A Sieving

  2. Ocular Gene Therapy Laboratory, National Eye Institute (NEI), National Institutes of Health (NIH), Rockville, MD, USA

    Z Wu & P Colosi

  3. National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD, USA

    P A Sieving

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  1. T K Park
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  2. Z Wu
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  3. S Kjellstrom
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  4. Y Zeng
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  5. R A Bush
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  6. P A Sieving
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  7. P Colosi
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Correspondence to P Colosi.

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Park, T., Wu, Z., Kjellstrom, S. et al. Intravitreal delivery of AAV8 retinoschisin results in cell type-specific gene expression and retinal rescue in the Rs1-KO mouse. Gene Ther 16, 916–926 (2009). https://doi.org/10.1038/gt.2009.61

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