QLT091001, a 9-<i>cis</i>-Retinal Analog, Is Well-Tolerated by Retinas of Mice with Impaired Visual Cycles

Maeda, Tadao; Dong, Zhiqian; Jin, Hui; Sawada, Osamu; Gao, Songqi; Utkhede, Deepank; Monk, Wendy; Palczewska, Grażyna; Palczewski, Krzysztof

doi:10.1167/iovs.12-11152

Cited by 38 publications

(27 citation statements)

References 59 publications

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“…[55][56][57] In RPGRIP1 knock-out mice, both improved outer segment morphology and photoreceptor survival, and better preservation of ERG responses have been demonstrated with RPGRIP1 gene replacement using both AAV2 and AAV8 vectors. 71 72 Improved photoreceptor function up to 24 months postsubretinal injection has also been shown in the canine model.…”

Section: Rpgrip1-associated Lcamentioning

confidence: 99%

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

et al. 2017

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Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70–80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention.

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Section: Rpgrip1-associated Lcamentioning

confidence: 99%

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

et al. 2017

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“…Indeed, administration of 9-cis-retinoid has been shown to bypass defects in the visual cycle, restore visual function and slow the progression of retinal degeneration in Lrat 2/2 and Rpe65 2/2 mice (Van Hooser et al 2000;Maeda et al 2009). Similarly, long-term treatment with the 9-cis-retinal analog QLT091001 was well-tolerated and able to maintain retinal thickness and morphology in Lrat 2/2 , Rpe65 2/2 mice and Gnat1 2/2 mice (Maeda et al 2013). Based on these encouraging preclinical results, a safety proof-of-concept study to evaluate the effects of oral QLT091001 in RP subjects with an autosomal dominant mutation in RPE65 is currently underway (see http:// ClinicalTrials.gov.…”

Section: Alternative Pharmacological Approachesmentioning

confidence: 89%

Clinical Characteristics and Current Therapies for Inherited Retinal Degenerations

Sahel

Marazova

Audo

2014

Cold Spring Harbor Perspectives in Medicine

188

155

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“…In disease marked by 11-cis-retinal deficiency, 9-cis-retinal can form iso-rhodopsin (37) and generate small light-evoked rod responses (38). The propensity for 9-cis-retinal to form cis-A2E likely explains the detection of some RPE autofluorescence in Rpe65 −/− mice (39).…”

Section: Discussionmentioning

confidence: 99%

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

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

111

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Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimerphosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4 −/− mice reared in cyclic light compared with darkness. In albino Abca4 −/− mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic lightreared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.bisretinoid | visual cycle | retina | retinal pigment epithelium | macular degeneration

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QLT091001, a 9-cis-Retinal Analog, Is Well-Tolerated by Retinas of Mice with Impaired Visual Cycles

Abstract: Retinas of Lrat(-/-), Rpe65(-/-), and crossbred Gnat1(-/-) mice tolerated prolonged high-dose QLT091001 treatment well.

Cited by 38 publications

References 59 publications

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions

Clinical Characteristics and Current Therapies for Inherited Retinal Degenerations

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

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