April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Exogenous COL18A1 Restores Retinal Function in a Patient Specific Model of Knobloch Syndrome
Author Affiliations & Notes
  • Huy V. Nguyen
    Columbia University College of Physicians and Surgeons, New York, NY
  • Yao Li
    Ophthalmology, Columbia University, New York, NY
  • Irene H Maumenee
    Illinois Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, NY
  • Stephen H Tsang
    Pathology and Cell Biology, Columbia University, New York, NY
  • Footnotes
    Commercial Relationships Huy Nguyen, None; Yao Li, None; Irene Maumenee, None; Stephen Tsang, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2982. doi:
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      Huy V. Nguyen, Yao Li, Irene H Maumenee, Stephen H Tsang; Exogenous COL18A1 Restores Retinal Function in a Patient Specific Model of Knobloch Syndrome. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2982.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Knobloch Syndrome (KNO, OMIM: 267750) is an autosomal recessive disorder characterized by high myopia, vitreoretinal degeneration with recurrent retinal detachment, and congenital encephalocele. The confirmed genetic mutation of the COL18A1 gene on 21q22.3 is responsible for the characteristic dysfunctional retinal pigment epithelium (RPE) cells. There is currently no approved treatment for KNO. In the current study, we aim to rescue KNO RPE function with exogenous COL18A1 using human induced pluripotent stem (iPS) cell technology.

Methods: Stem cells were generated from skin fibroblast from a patient with KNO. Antibodies against standard pluripotency markers Oct-4, Sox-2, TRA-1-60, SSEA4, and NANOG were applied to characterize the iPS cells reprogrammed from this sample. Stem cells were differentiated into morphological and functional RPE cells, as shown by immunohistochemical staining, transmission electron microscopy, and measurement of transepithelial resistance (TER). iPS-derived RPE were seeded onto Transwell membranes and grown on Matrigel matrix. Exogenous COL18A1 was applied to the Matrigel matrix and TER of experimental RPE was compared to that of untreated KNO-iPS-derived RPE and wildtype iPS-derived RPE.

Results: KNO-iPS-derived RPE lacking COL18A1 is dysmorphologic. Application of exogenous COL18A1 to the Matrigel matrix restored KNO-iPS-derived RPE morphology to that of wildtype iPS-derived RPE in a dose-dependent manner. TER levels of untreated KNO-iPS-derived RPE were extinguished while TER levels of COL18A1-treated KNO-iPS-derived RPE approached that of control RPE.

Conclusions: This is the first report of human iPS-derived RPE being successfully used to model this disease phenotype. The results indicate that exogenous COL18A1 can successfully be applied to restore morphology and function of KNO-iPS-derived RPE.

Keywords: 701 retinal pigment epithelium • 721 stem cells • 538 gene transfer/gene therapy  

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