AAV-Mediated Gene Therapy for Retinal Degeneration in the<i>rd10</i>Mouse Containing a Recessive PDEβ Mutation

Pang, Jijing; Boye, Sanford L.; Kumar, Ashok; Dinculescu, Astra; Deng, Wen‐Tao; Li, Jie; Li, Qiuhong; Rani, Asha; Foster, Thomas C.; Chang, Bo; Hawes, Norman L.; Boatright, Jeffrey H; Hauswirth, William W.

doi:10.1167/iovs.07-1622

Cited by 133 publications

(127 citation statements)

References 27 publications

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“…In mice, there is an extensive literature on gene augmentation therapy showing improved photoreceptor survival as long as the intervention is applied before or at very early stages of retinal degeneration (43)(44)(45)(46)(47). Other work has shown positive effects of gene therapy when applied to disorganized retinas with rosettes (48).…”

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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“…Rod-and cone-mediated behavior was assessed using Morris Water Maze as previously described (Pang et al, , 2008. Testing consisted of four blocks of three trials per day for four consecutive days under each respective lighting condition.…”

Section: Morris Water Maze Testingmentioning

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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“…[3][4][5] In addition, therapeutic modalities have been demonstrated for other genetic subtypes of RP and LCA in a growing number of animal models, both of recessive and dominant forms of disease. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Notwithstanding such progress, the genetic complexity of this group of diseases represents a formidable logistic and economic hurdle in developing viable methods of prevention. Given this caveat, parameters effecting photoreceptor survival that are independent of the primary genetic lesion are critically important to identify.…”

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confidence: 99%

C1q enhances cone photoreceptor survival in a mouse model of autosomal recessive retinitis pigmentosa

et al. 2011

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Retinitis pigmentosa (RP) is a degenerative retinal disease involving progressive loss of rod and cone photoreceptor function. It represents the most common form of registered blindness among the working aged populations of developed countries. Given the immense genetic heterogeneity associated with this disease, parameters influencing cone photoreceptor survival (preservation of daytime vision) that are independent of primary mutations are exceedingly important to identify from a therapeutic standpoint. Here we identify C1q, the primary component of the classical complement pathway, as a cone photoreceptor neuronal survival factor. European Journal of Human Genetics (2012) 20, 64-68; doi:10.1038/ejhg.2011; published online 24 August 2011Keywords: C1qa; C3; retinopathy; retinitis pigmentosa; complement; cone photoreceptors INTRODUCTION Hereditary retinopathies, prominent among which is retinitis pigmentosa (RP), conditions involving progressive death of photoreceptors are amongst the most genetically heterogeneous of any group of mendelian conditions. Including Leber's congenital amaurosis (LCA), a congenital retinopathy with pathological features bearing similarities to RP, 60 genes have now been implicated in disease etiology. If syndromic forms of disease and other hereditary retinopathies are included, 202 genetic loci have been identified and a total of 161 genes so far characterized. 1 RP segregates largely in an autosomal dominant, recessive, or X-linked recessive manner, 2 whereas all of the 16 genetic forms of LCA that have been identified to date are autosomal recessive; hence, gene therapies require strategies based either on gene replacement, or on the selective suppression of dominantly mutated genes, or their transcripts. Progress is being made to the extent that clinical trials involving AAV-mediated gene replacement have now been established for one form of LCA caused by mutations within the RPE65 gene. [3][4][5] In addition, therapeutic modalities have been demonstrated for other genetic subtypes of RP and LCA in a growing number of animal models, both of recessive and dominant forms of disease. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Notwithstanding such progress, the genetic complexity of this group of diseases represents a formidable logistic and economic hurdle in developing viable methods of prevention. Given this caveat, parameters effecting photoreceptor survival that are independent of the primary genetic lesion are critically important to identify. It has emerged over the last 5 or so years that major pathological features involving sub-retinal drusen deposition and choroidal neovascularization that are associated with one form of multifactorial retinopathy, namely age-related macular degeneration, where the central cone-rich part of the retina, or macula, degenerates, can now be explained, at least in part, by excessive complement activity on ocular surfaces. [24][25][26][27][28][29][30] However, the influence of complement on cone photoreceptor survival is...

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AAV-Mediated Gene Therapy for Retinal Degeneration in therd10Mouse Containing a Recessive PDEβ Mutation

Cited by 133 publications

References 27 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

C1q enhances cone photoreceptor survival in a mouse model of autosomal recessive retinitis pigmentosa

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