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Improvement of Central Visual Function in Retinal Degeneration Slow Mice through Gene Therapy
1Schlichtenbrede F. C., 2Sarra G.-M., 1Bainbridge J. W. B., 3Salt T., 1Ali R. R.,
1Institute of Ophthalmology, University College London, Dept. Molecular Genetics (London)
2Universitätsspital Bern, Augenklinik (Bern)
3Institute of Ophthalmology, University College London, Dept. Visual Science (London)
Purpose: The retinal degeneration slow (rds or Prph2Rd2/Rd2) mouse, a model of recessive retinitis pigmentosa, lacks a functional gene encoding peripherin 2, which is required for the formation of photoreceptor outer segment discs. We have previously demonstrated restoration of photoreceptor ultrastructure and function by adeno-associated virus (rAAV) mediated gene transfer of peripherin 2. Here we have extended our assessment to central visual neuronal responses in order to show an improvement of central visual function.
Method: rAAV encoding the Prph2-transgene was injected subretinally into one eye of 10 rds-mice on postnatal day10. Three to 5 weeks later electroretinograms (ERGs) were performed to demonstrate retinal rescue. Four mice were used to record central visual responses of neurons in the superior colliculus. Visual stimuli were presented on a CRT screen as moving bars or flashing spots of varying luminance. For both methods the untreated contralateral eye served as control.
Results: Simultaneous ERGs of right and left eyes showed a substantial increase in b-wave amplitude and improvement in waveform on the treated side. This effect was first noted three weeks post injection and persisted for up to 12 weeks, showing good retinal responses on the treated side and low residual responses contralaterally. Recordings from visually responsive neurons in the superior colliculus showed clear responses to stimuli and a significant reduction in stimulus threshold as compared to recordings on the untreated contralateral side.
Conclusions: These findings suggest that gene replacement therapy not only restores photoreceptor morphology and function in the rds mouse, but also improves central visual responses.