Figure 1. Strategy that allows evaluation of the point of no return for gene therapy to treat retinal degeneration.

(A) Schematic of the genetic strategy developed by Koch et al. (21) to stimulate photoreceptor degeneration and evaluate the effect of rescuing the defect on demand by injecting the mouse with tamoxifen at different points during disease progression. The mouse has two different Pde6b alleles. One allele produces a mostly inactive protein as the result of an H620Q substitution. The other allele is normal, but it is interrupted by a floxed stop cassette. The very low PDE6 activity in the retinae of these mice causes rod photoreceptors to degenerate. (B) The Pde6g promoter is used to express CreERT2 in rods, and when the mouse is injected with tamoxifen, CreERT2 is activated and able to excise the stop cassette, resulting in expression of active PDE6. (C) In the absence of intervention, photoreceptors degenerate over time, resulting in vision loss. Tamoxifen-induced expression of active PDE6 at four or eight weeks of age halts degeneration. Although not shown in this schematic, the retinae continued to be stable out to 52 weeks of age.