Our group studies disease mechanisms in inherited retinal degenerations (IRDs), and evaluates efficacy and safety of potential treatments. IRDs result in vision loss due to mutations in more than 200 different genes and include diagnoses such as Retinitis Pigmentosa, Stargardt Disease, Leber Congenital Amarousis, and others. There are multitudes of different pathological mechanisms resulting from different mutations. Our group uses non-invasive tests to link changes in retinal structure and function to underlying molecular pathology. We also develop and evaluate novel outcome measures for use in clinical trials.
March 5, 2018: Paper Published in Proc. Natl. Acad. Sci., USA
Macular degenerations cause loss of central vision that allows us to distinguish fine details and read fine print in day light. Unlike the multifactorial age-related forms, monogenic macular degenerations are caused by mutations in a gene and cause visual disability early in life. Mutations in BEST1 cause a spectrum of macular degenerations collectively called bestrophinopathies. Mutations in the same gene also cause macular degeneration in dogs. In both human and canine forms, the cone-photoreceptor rich fovea at the center of the macula is disrupted first in bestrophinopathies.
We now show that the canine macular degeneration caused by BEST1 mutation is treated successfully with gene therapy. We also show that dogs have a microscopic separation between the photoreceptors and the RPE, and the extent of this separation is widened by light exposure. Gene therapy also ameliorates this retina-wide defect and brings the photoreceptors into apposition with the RPE. In patients, we show that a microscopic separation between the photoreceptors and the RPE is associated with a dramatic slowing of the rate of vitamin A diffusion between them.
Guziewicz KE, Cideciyan AV, Beltran WA, Komaromy AM, Dufour VL, Swider M, Iwabe S, Sumaroka A, Kendrick BT, Ruthel G, Chiodo VA, Heon E, Hauswirth WW, Jacobson SG, Aguirre GD. BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure. Proc. Natl. Acad. Sci. USA, in press, 2018. [UPenn Press Release]
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