Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

Petit, Lolita; Lhériteau, Elsa; Weber, Michel; Meur, Guylène Le; Deschamps, Jack-Yves; Provost, Nathalie; Mendes-Madeira, Alexandra; Libeau, Lyse; Guihal, Caroline; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

doi:10.1038/mt.2012.134

Cited by 59 publications

(51 citation statements)

References 44 publications

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“…In naturally occurring canine models, both of RPE65-LCA and others, gene therapy has produced similar results: intervention after the onset of photoreceptor degeneration has not been able to modify the natural history of the disease (16) or to restore visual function unless adjunctive treatments are done (40). When the intervention preceded major loss of photoreceptors, prevention of retinal degeneration has often been achieved (16,30,41,42) but not always (17).…”

Section: Discussionmentioning

confidence: 99%

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Beltran

Cideciyan

Iwabe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.

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Section: Discussionmentioning

confidence: 99%

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Beltran

Cideciyan

Iwabe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Despite this advantage over AAV5 within rodents, a recent study performed in PDE6b mutant dogs indicated that AAV5 and AAV8 were equally suitable for conferring therapy (Petit et al, 2012). Ultimately, the choice of serotype for clinical treatment of LCA1 (and perhaps other photoreceptor-mediated diseases) will depend on its ability to transduce photoreceptors in the primate (and the relative toxicities of the vectors, once tested).…”

Section: Discussionmentioning

confidence: 99%

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

et al. 2013

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Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1). GUCY2D encodes photoreceptor-specific, retinal guanylate cyclase-1 (RetGC1). Reports of retinal degeneration in LCA1 are conflicting; some describe no obvious degeneration and others report loss of both rods and cones. Proof of concept studies in models representing the spectrum of phenotypes is warranted. We have previously demonstrated adeno-associated virus (AAV)-mediated RetGC1 is therapeutic in GC1ko mice, a model exhibiting loss of cones only. The purpose of this study was to characterize AAV-mediated gene therapy in the RetGC1/RetGC2 double knockout (GCdko) mouse, a model lacking rod and cone function and exhibiting progressive loss of both photoreceptor subclasses. Use of this model also allowed for the evaluation of the functional efficiency of transgenic RetGC1 isozyme. Subretinal delivery of AAV8(Y733F) vector containing the human rhodopsin kinase (hGRK1) promoter driving murine Gucy2e was performed in GCdko mice at various postnatal time points. Treatment resulted in restoration of rod and cone function at all treatment ages and preservation of retinal structure in GCdko mice treated as late as 7 weeks of age. Functional gains and structural preservation were stable for at least 1 year. Treatment also conferred cortical-and subcortical-based visually-guided behavior. Functional efficiency of transgenic RetGC1 was indistinguishable from that of endogenous isozyme in congenic wild-type (WT) mice. This study clearly demonstrates AAV-mediated RetGC1 expression restores function to and preserves structure of rod and cone photoreceptors in a degenerative model of retinal guanylate cyclase deficiency, further supporting development of an AAV-based vector for treatment of LCA1.

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“…In addition, we evaluated AAV2/8 in combination with regulatory elements known to efficiently transduce rods. We selected both the ubiquitous cytomegalovirus (CMV) promoter, which is known to allow efficient RPE and PR transduction in different species (Bennett et al, 1999;Lai et al, 2004;Allocca et al, 2007;Mussolino et al, 2011), and the human rhodopsin kinase 1 (GRK1) promoter that drives PRspecific gene expression in both rods and cones (Young et al, 2003;Allocca et al, 2007;Khani et al, 2007;Pawlyk et al, 2010;Sun et al, 2010;Beltran et al, 2012;Boye et al, 2012;Petit et al, 2012). As an additional strategy to restrict transgene expression to PRs, we used the CMV promoter in combination with target sites of microRNA (miR) 204, which is expressed at higher levels in the RPE than in PRs (Karali et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Combined Rod and Cone Transduction by Adeno-Associated Virus 2/8

et al. 2013

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Gene transfer to both cone and rod photoreceptors (PRs) is essential for gene therapy of inherited retinal degenerations that are caused by mutations in genes expressed in both PR types. Vectors based on the adenoassociated virus (AAV) efficiently transduce PRs of different species. However, these are predominantly rods and little is known about the ability of the AAV to transduce cones in combination with rods. Here we show that AAV2/8 transduces pig cones to levels that are similar to AAV2/9, and the outer nuclear layer (mainly rods) to levels that are on average higher, although not statistically significant, than both AAV2/5 and AAV2/9. We additionally found that the ubiquitous cytomegalovirus (CMV), but not the PR-specific GRK1 promoter, transduced pig cones efficiently, presumably because GRK1 is not expressed in pig cones as observed in mice and humans. Indeed, the GRK1 and CMV promoters transduce a similar percentage of murine cones with the CMV reaching the highest expression levels. Consistent with this, the AAV2/8 vectors with either the CMV or the GRK1 promoter restore cone function in a mouse model of Leber congenital amaurosis type 1 (LCA1), supporting the use of AAV2/8 for gene therapy of LCA1 as well as of other retinal diseases requiring gene transfer to both PR types.

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Restoration of Vision in the pde6β-deficient Dog, a Large Animal Model of Rod-cone Dystrophy

Cited by 59 publications

References 44 publications

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

Combined Rod and Cone Transduction by Adeno-Associated Virus 2/8

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