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

Abstract

The retinal degeneration slow (rds or Prph2(Rd2/Rd2)) mouse, a model of recessive 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-term effect of gene replacement therapy using an adeno-associated (AAV) vector and demonstrated induction of outer segments and improvement of photoreceptor function. Here we have extended our analysis and have demonstrated that the potential for ultrastructural improvement is dependent upon the age at which animals are treated, but the effect of a single injection on photoreceptor ultrastructure may be long-term. However, there was no significant effect on photoreceptor cell loss, irrespective of the date of administration, 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 restoration, but suggested that transgene over-expression is of significance. These findings suggest that successful gene therapy in patients with photoreceptor defects may ultimately depend upon intervention in early stages of disease and upon accurate control of transgene expression.

Long-term preservation of retinal function in the RCS rat model of retinitis pigmentosa following lentivirus-mediated gene therapy

“…This has not yet been possible for treatment of animal models, such as the rds mouse, that have severe photoreceptor defects. 20 Preclinical trials of gene therapy for a type of Lebers congenital amaurosis (LCA), a severe form of early-onset retinal dystrophy, due to mutations in the RPE-specific RPE65 have been particularly successful 3,21 and clinical trials of gene therapy to treat this defect are likely to be the first such trials for the treatment of retinal dystrophies. This is because this gene defect results in a severe condition and delivery to the RPE of an RPE65 transgene resulting in restoration of absent rod photoreceptor function would provide an early functional readout, long before the effect on retinal degeneration might be assessed.…”

Recombinant AAV-mediated gene transfer to the retina: gene therapy perspectives

“…35,74,75 Extended analysis of this gene therapy treatment in the same model demonstrated that the potential for ultrastructural improvement is dependent upon the age at which animals are treated and that overexpression of the prph 2 might be harmful to photoreceptor cells. 76 The Royal College of Surgeons (RCS) rat is a widely studied animal model of retinal degeneration in which the inability of the RPE to phagocytose shed photoreceptor outer segments leads to a progressive loss of rod and cone photoreceptors. The defect, which has also been described in patients with retinitis pigmentosa, 77 results from a mutation in the mertk gene, which is normally expressed in the RPE.…”

Gene supplementation therapy for recessive forms of inherited retinal dystrophies

“…33 EARLY PROOF-OF-PRINCIPLE FOR GENE SUPPLEMENTATION THERAPY FOR RETINAL DYSTROPHY Although earlier studies had shown limited efficacy of gene supplementation in the Rd1 murine model of retinal degeneration, which has a defect in the Pde6b gene, [34][35][36][37] the first definitive proof-of-concept for gene supplementation therapy for a photoreceptor cell defect was demonstrated in the Rds mouse, which has a naturally occurring null mutation in the Prph2 gene. 38,39 Subretinal injection of AAV2 carrying the murine Prph2 gene under control of the bovine rhodopsin promoter results in expression of the structural outer segment protein Peripherin 2 and the formation of photoreceptor cell outer segments that are otherwise absent in this mouse model. The generation of outer segments is associated with restoration of the electroretinogram (ERG) 38 to B25% of wild-type levels, and improvement of neuronal responses measured in the superior colliculus.…”

“…The generation of outer segments is associated with restoration of the electroretinogram (ERG) 38 to B25% of wild-type levels, and improvement of neuronal responses measured in the superior colliculus. 40 However, despite significant improvement of photoreceptor cell function in these mice, the duration of functional benefit is limited by progressive photoreceptor degeneration 39 that may be a consequence of insufficiently rapid onset of AAV2-mediated transgene expression or non-physiological levels of Peripherin 2 production. This partially successful rescue of a photoreceptor cell defect was followed by the first effective intervention in a retinal dystrophy caused by an RPE defect.…”