Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait

Wright, Alan F.; Chakarova, Christina; El-Aziz, Mai M. Abd; Bhattacharya, Siladitya

doi:10.1038/nrg2717

Cited by 513 publications

(483 citation statements)

References 142 publications

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“…X-linked RP caused by mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene is one of the most common inherited retinal degenerations (18)(19)(20). There are currently more than 300 distinct mutations (rpgr.hgu.mrc.ac.uk/supplementary/) identified in RPGR, and the majority are found in a glutamic acidrich domain within exon ORF15 (21,22).…”

Section: Significancementioning

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: Significancementioning

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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“…Many genes that cause nonsyndromic RP have also been associated with other retinal diseases such as Leber congenital amaurosis (LCA), Bardet Biedl syndrome (BBS), Usher syndrome, cone rod dystrophy, and Stargardt disease (3,(16)(17)(18)(19). To investigate the possibility that the Alu insertion in MAK is also involved in any of these phenotypes, we screened 454 probands with LCA, 125 probands with BBS, 109 probands with Usher syndrome, 175 probands with cone rod dystrophy, and 202 probands with Stargardt disease.…”

Section: Alu Insertion In Mak Is Not Associated With Other Photoreceptormentioning

confidence: 99%

“…Mutations in genes that encode critical components of the outer segment apparatus are common causes of photoreceptor loss (2), and such loss often leads to night blindness, constricted visual fields, intraretinal pigmentation, and electrophysiological abnormalities, which are recognized clinically as retinitis pigmentosa (RP). It is estimated that mutations in more than 100 genes will eventually be shown to cause this phenotype (3,4). At present, fewer than one-half of these mutations have been identified (4).…”

mentioning

confidence: 99%

Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase ( MAK ) as a cause of retinitis pigmentosa

Tucker

Scheetz

Mullins

et al. 2011

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

188

191

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Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non-MAK-associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies.

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“…1 IRDs are a diverse group of conditions that result from mutations in any one of over 250 different genes, with the most common form being retinitis pigmentosa (RP). 2 Despite the great diversity of mutations, RP converges on a phenotype of photoreceptor cell loss in later stages of the disease. Studies of post-mortem retinas from patients with RP have shown that a large percentage of inner retinal neurons remain present even after photoreceptor degeneration.…”

Section: Introductionmentioning

confidence: 99%

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

et al. 2017

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The majority of inherited retinal degenerations converge on the phenotype of photoreceptor cell death. Second-and third-order neurons are spared in these diseases, making it possible to restore retinal light responses using optogenetics. Viral expression of channelrhodopsin in the third-order neurons under ubiquitous promoters was previously shown to restore visual function, albeit at light intensities above illumination safety thresholds. Here, we report (to our knowledge, for the first time) activation of macaque retinas, up to 6 months post-injection, using channelrhodopsin-Ca 2+ -permeable channelrhodopsin (CatCh) at safe light intensities. High-level CatCh expression was achieved due to a new promoter based on the regulatory region of the gamma-synuclein gene (SNCG) allowing strong expression in ganglion cells across species. Our promoter, in combination with clinically proven adeno-associated virus 2 (AAV2), provides CatCh expression in peri-foveolar ganglion cells responding robustly to light under the illumination safety thresholds for the human eye. On the contrary, the threshold of activation and the proportion of unresponsive cells were much higher when a ubiquitous promoter (cytomegalovirus [CMV]) was used to express CatCh. The results of our study suggest that the inclusion of optimized promoters is key in the path to clinical translation of optogenetics.

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Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait

Cited by 513 publications

References 142 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

Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase ( MAK ) as a cause of retinitis pigmentosa

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

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