Gene replacement therapy in the retinal degeneration slow (rds)mouse: the effect on retinal degeneration following partial transduction of the retina

The retinal degeneration slow (rds or Prph2(Rd2/Rd2)) mouse, a model of rec essive retinitis pigmentosa, lacks a functional gene encoding peripherin 2. This membrane glycoprotein is required for the formation of photoreceptor outer segment discs. The striking feature of the rds mouse is the complete failure to develop outer segments. We have previously examined the short-te rm effect of gene replacement therapy using an adeno-associated (AAV) vecto r and demonstrated induction of outer segments and improvement of photorece ptor function. Here we have extended our analysis and have demonstrated tha t the potential for ultrastructural improvement is dependent upon the age a t which animals are treated, but the effect of a single injection on photor eceptor ultrastructure may be long-term. However, there was no significant effect on photoreceptor cell loss, irrespective of the date of administrati on, despite the improvements in morphology and function. Our investigation excluded procedure-related damage, vector toxicity and immune responses as major factors which might counteract the benefits of photoreceptor restorat ion, but suggested that transgene over-expression is of significance. These findings suggest that successful gene therapy in patients with photorecept or defects may ultimately depend upon intervention in early stages of disea se and upon accurate control of transgene expression.