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J. W. B. Bainbridge, A. J. Smith, G. S. Rubin, S. Robbie, F. W. Fitzke, G. E. Holder, A. Stockman, I. van den Born, T. Moore, R. R. Ali; Clinical Trial of Gene Therapy for Early Onset Severe Retinal Dystrophy Caused by Defects in RPE65. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4493.
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Recombinant adeno-associated virus (rAAV) vector-mediated gene replacement therapy can improve retinal function and visual behaviour in human subjects with defects in the gene encoding the RPE isomerase RPE65. The purpose of this clinical trial is to further investigate the safety and efficacy of gene therapy for retinal dystrophy caused by RPE65 mutations.
In a phase I/II dose-escalation trial, we have delivered subretinally recombinant adeno-associated virus (rAAV) vector expressing RPE65 under the control of an RPE65 promoter in 7 human subjects with early onset severe retinal dystrophy associated with mutations in RPE65. We have examined systemic vector dissemination and immune responses following vector delivery, assessed visual function pre- and post- vector delivery using a range of psychophysical techniques, and performed detailed electrophysiology and retinal imaging studies.
There have been no serious adverse effects of surgical delivery of vector in the subjects enrolled to date. We have detected no systemic dissemination of vector genome. We have detected an increase in systemic neutralising antibodies to AAV capsid in one subject but no evidence of immune responses to RPE65 proteins. We have measured significant improvements in retinal sensitivity by microperimetry and dark-adapted perimetry, and improved performance in a test of visually-guided mobility.
The outcomes in the first 7 subjects to date suggest that subretinal delivery of rAAV vector can be safe in humans in the short term and can improve retinal sensitivity.
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