It's never too late to save a photoreceptor

Abstract

Recent gene therapy progress has raised the possibility that vision loss caused by inherited retinal degeneration can be slowed or prevented. Unfortunately, patients are not usually diagnosed until enough degeneration has occurred that the deterioration in vision is noticeable. Therefore, effective gene therapy must halt degeneration to stabilize and preserve any remaining vision. Gene therapy methods currently in human clinical trials rely on subretinal or intravitreal injections of adeno-associated virus to deliver the therapeutic gene. To date, long-term results in patients treated with subretinal injections for Leber congenital amaurosis have been mixed. Proposed limitations include variability in the gene delivery method and a possible point of no return, at which treatment would be ineffective. In this issue of the JCI, Koch et al. describe a well-controlled and precise mouse model for testing the ability of gene therapy to halt the progress of degeneration. Instead of viral-mediated therapeutic gene delivery, the authors induced expression of an integrated transgene at specific times during the course of photoreceptor degeneration. In Pde6b-deficient retina, this strategy halted degeneration, even when more than 70% of photoreceptors had already degenerated. The results of this study demonstrate that retinal degeneration can be stopped, even at late stages of disease.

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.