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J T. Stout, David J. Wilson, Richard Weleber, Mark Pennesi, Maureen Toomey, Peter Francis, Jose A. Sahel, Jr., Isabelle Audo, Saddek Mohand-Said, Stuart M. Naylor; Lentiviral Vector Gene Replacement Therapy in Stargardt Disease and Usher Syndrome type Ib. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1936.
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Single gene disorders are responsible for several conditions that lead to profound vision loss including Stargardt disease and Ushers syndrome. These diseases may be amenable to gene replacement therapy and trials are underway to evaluate safety and efficacy of this therapeutic approach. The purpose of this report is to describe the surgical technique and endpoint determination for lentiviral vectors based on an EIAV-based platform in treating inherited retinal degenerations.
Phase I/II trials are designed principally to evaluate the safety and efficacy of gene replacement therapy in patients with Stargardt Disease and Usher Syndrome type 1b. Eligible patients must have disease-causing mutations on both chromosomes, confirmed by segregation analysis, for the gene ABCA4 (Stargardt disease) or MYO7A (Usher 1B). Study design is that of dose escalation to determine safety in an initial cohort followed by efficacy assessment in subsequent cohorts. Lentiviral vectors (EIAV-ABCA4 for Stargardt, EIAV-MYO7A Usher 1b) are administered subretinally following vitrectomy and efficacy endpoints consist of visual acuity, OCT, GATE visual field, multifocal and full field ERG and spacing of the cone mosaic (as assessed with adaptive optics).
The Stargardt disease trial is underway following FDA and AFSSAPS approval, FDA approval has also been received for the Usher trial. Thus far, subretinal fluid reabsorption has been rapid and complete and without inflammatory consequence.
No toxicity has been noted in Stargardt disease patients undergoing gene replacement therapy with EIAV-ABCA4 in the first cohort. The lentiviral vector platform has the potential advantage of permanent expression of gene products implicated in retinal disease and in particular those that are too large for other available vectors.
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