Blind dogs that can see: pharmacological treatment of Leber congenital amaurosis caused by a defective visual cycle.
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ABSTRACT:
SUBMITTER: Palczewski K
PROVIDER: S-EPMC4495581 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundLeber congenital amaurosis (LCA), a heterogeneous early-onset retinal dystrophy, accounts for approximately 15% of inherited congenital blindness. One cause of LCA is loss of the enzyme lecithin:retinol acyl transferase (LRAT), which is required for regeneration of the visual photopigment in the retina.Methods and findingsAn animal model of LCA, the Lrat-/- mouse, recapitulates clinical features of the human disease. Here, we report that two interventions--intraocular gene therapy and oral pharmacologic treatment with novel retinoid compounds--each restore retinal function to Lrat-/- mice. Gene therapy using intraocular injection of recombinant adeno-associated virus carrying the Lrat gene successfully restored electroretinographic responses to approximately 50% of wild-type levels (p < 0.05 versus wild-type and knockout controls), and pupillary light responses (PLRs) of Lrat-/- mice increased approximately 2.5 log units (p < 0.05). Pharmacological intervention with orally administered pro-drugs 9-cis-retinyl acetate and 9-cis-retinyl succinate (which chemically bypass the LRAT-catalyzed step in chromophore regeneration) also caused long-lasting restoration of retinal function in LRAT-deficient mice and increased ERG response from approximately 5% of wild-type levels in Lrat-/- mice to approximately 50% of wild-type levels in treated Lrat-/- mice (p < 0.05 versus wild-type and knockout controls). The interventions produced markedly increased levels of visual pigment from undetectable levels to 600 pmoles per eye in retinoid treated mice, and approximately 1,000-fold improvements in PLR and electroretinogram sensitivity. The techniques were complementary when combined.ConclusionIntraocular gene therapy and pharmacologic bypass provide highly effective and complementary means for restoring retinal function in this animal model of human hereditary blindness. These complementary methods offer hope of developing treatment to restore vision in humans with certain forms of hereditary congenital blindness.
| S-EPMC1274279 | biostudies-literature
Project description:To determine the intervisit variability of kinetic visual fields and visual acuity in patients with Leber congenital amaurosis (LCA) caused by mutations in the RPE65 (Retinal Pigment Epithelium-specific protein 65kDa) gene.RPE65-LCA patients (n = 20; ages 11-40 years) were studied on at least two visits separated by fewer than 120 days using Goldmann visual field (GVF) and ETDRS visual acuity (VA) in a retrospective review. GVFs were quantified by computing the spherical coordinates of their vertices and calculating the solid angle subtended, and reported in normalized solid-angle units (nsu) as a percentage of average normal field extent. Repeatability coefficients were calculated using 95% confidence intervals on log(10)-converted variables.Visual field extents in RPE65-LCA spanned a wide range from 4 to 95 nsu. The repeatability coefficient was 0.248 (log(10)nsu), suggesting cutoffs for significant change (in nsu) of +77% for improvement and -44% for worsening. VA in RPE65-LCA ranged from logMAR = 0.14 to 1.96 (20/40 to 20/1250). The repeatability coefficient was 0.170 (logMAR) (±8.5 ETDRS letters). Comparisons with published studies of ungenotyped retinitis pigmentosa showed that the RPE65-LCA patients had higher variability in kinetic field extent. VA variability in RPE65-LCA fell within reported results for retinitis pigmentosa.Variability data for GVF and VA are provided to permit interpretation of the significance of increases and decreases of these functional outcomes in ongoing and planned clinical trials of therapy for LCA caused by RPE65 mutations.
| S-EPMC3597193 | biostudies-literature
Project description:To study the topography of photoreceptor loss early in the course of Leber congenital amaurosis (LCA) caused by RPE65 mutations.Young patients with RPE65-LCA (n = 9; ages, 6-17 years) were studied with optical coherence tomography (OCT) in a wide region of central retina. Outer nuclear layer (ONL) thickness was mapped topographically and compared with that in normal subjects and in older patients with RPE65-LCA.Photoreceptor layer topography was abnormal in all young patients with RPE65-LCA. Foveal and extrafoveal ONL was reduced in most patients. There were interindividual differences, with ONL thicknesses at most retinal locations ranging from near the detectability limit to a significant fraction of normal. These differences were not clearly related to age. In most patients, there was a thinner ONL inferior to the fovea compared with that in the superior retina. Summary maps obtained by aligning and averaging photoreceptor topography across all young patients showed a relative preservation of ONL in the superior-temporal and temporal pericentral retina. These retinal regions also showed the greatest magnitude of interindividual variation.Photoreceptor loss in the foveal and extrafoveal retina was prominent, even in the youngest patients studied. Differences in the topography of residual photoreceptors in children with RPE65-LCA suggest that it may be advisable to use individualized ONL mapping to guide the location of subretinal injections for gene therapy and thereby maximize the potential for efficacy.
| S-EPMC2731624 | biostudies-other
Project description:Leber congenital amaurosis (LCA) is an infantile-onset form of inherited retinal degeneration characterized by severe vision loss(1,2). Two-thirds of LCA cases are caused by mutations in 17 known disease-associated genes(3) (Retinal Information Network (RetNet)). Using exome sequencing we identified a homozygous missense mutation (c.25G>A, p.Val9Met) in NMNAT1 that is likely to be disease causing in two siblings of a consanguineous Pakistani kindred affected by LCA. This mutation segregated with disease in the kindred, including in three other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD(+)) biosynthesis(4,5). Functional studies showed that the p.Val9Met alteration decreased NMNAT1 enzyme activity. Sequencing NMNAT1 in 284 unrelated families with LCA identified 14 rare mutations in 13 additional affected individuals. These results are the first to link an NMNAT isoform to disease in humans and indicate that NMNAT1 mutations cause LCA.
| S-EPMC3454532 | biostudies-literature
Project description:To evaluate changes in visual acuity (VA) over time in patients with Leber congenital amaurosis (LCA) and mutations in the CEP290 gene.Visual acuity was determined at the initial and most recent visits of 43 patients with LCA and CEP290 mutations. The main outcome measures included the best-corrected VA at the initial and most recent visits, as well as the correlation between age and VA.At the initial visit, 14 patients had measurable chart VA in the better-seeing eye, 25 patients had nonmeasurable chart VA, and 4 young patients did not have VA assessed. At the most recent visit, 15 patients had measurable chart VA and 28 had nonmeasurable chart VA. The average interval between the 2 visits was 10.4 years (range, 2-47 years). For patients with measurable chart VA, the median logMAR value at the initial visit (0.75; range, 0.10-2.30) and at the most recent visit (0.70; range, 0.10-2.00) did not differ significantly (P> .05). There was no significant relationship between VA and age.Patients with LCA and CEP290 mutations had a wide spectrum of VA that was not related to age or length of follow-up. Severe VA loss was observed in most, but not all, patients in the first decade. These data will help clinicians provide counseling on VA changes in patients with CEP290 mutations and could be of value for future treatment trials.
| S-EPMC3688627 | biostudies-literature
Project description:Gene augmentation therapy is being planned for GUCY2D-associated Leber congenital amaurosis (LCA). To increase our understanding of the natural history of GUCY2D-LCA, patients were evaluated twice with an interval of 4 to 7 years between visits using safety and efficacy outcome measures previously determined to be useful for monitoring this disorder. In this group of molecularly-identified LCA patients (n = 10; ages 7-37 years at first visit), optical coherence tomography (OCT) was used to measure foveal cone outer nuclear layer (ONL) thickness and rod ONL at a superior retinal locus. Full-field stimulus testing (FST) with chromatic stimuli in dark- and light-adapted states was used to assay rod and cone vision. Changes in OCT and FST over the interval were mostly attributable to inter-visit variability. There were no major negative changes in structure or function across the cohort and over the intervals studied. Variation in severity of disease expression between patients occurs; however, despite difficulties in quantifying structure and function in such seriously visually impaired individuals with nystagmus, the present work supports the use of OCT as a safety outcome and FST as an efficacy outcome in a clinical trial of GUCY2D-LCA. A wide age spectrum for therapy was confirmed, and there was relative stability of structure and function during a typical time interval for clinical trials.
| S-EPMC7922686 | biostudies-literature
Project description:BACKGROUND:Peripapillary sparing is a characteristic that is traditionally described as pathognomonic for Stargardt disease. MATERIALS AND METHODS:We present a multimodal assessment of four Leber congenital amaurosis (LCA) cases with congenital macular atrophy and severely attenuated electroretinogram findings caused by bilallelic mutations in RDH12. RESULTS:Fundus autofluorescence imaging revealed a general loss of retinal pigment epithelium across the macula except for the peripapillary region in both eyes of all patients. Spectral domain-optical coherence tomography confirmed relative preservation in this area along with retinal thinning and excavation throughout the rest of the macula. LCA was diagnosed based on clinical exam and retinal imaging, and subsequently confirmed with genetic testing. CONCLUSIONS:Peripapillary sparing is a novel phenotypic feature of RDH12-associated LCA.
| S-EPMC6314194 | biostudies-literature
Project description:Leber congenital amaurosis 9 (LCA9) is an autosomal recessive retinal degeneration condition caused by mutations in the NAD(+) biosynthetic enzyme NMNAT1. This condition leads to early blindness but no other consistent deficits have been reported in patients with NMNAT1 mutations despite its central role in metabolism and ubiquitous expression. To study how these mutations affect NMNAT1 function and ultimately lead to the retinal degeneration phenotype, we performed detailed analysis of LCA-associated NMNAT1 mutants, including the expression, nuclear localization, enzymatic activity, secondary structure, oligomerization, and promotion of axonal and cellular integrity in response to injury. In many assays, most mutants produced results similar to wild type NMNAT1. Indeed, NAD(+) synthetic activity is unlikely to be a primary mechanism underlying retinal degeneration as most LCA-associated NMNAT1 mutants had normal enzymatic activity. In contrast, the secondary structure of many NMNAT1 mutants was relatively less stable as they lost enzymatic activity after heat shock, whereas wild type NMNAT1 retains significant activity after this stress. These results suggest that LCA-associated NMNAT1 mutants are more vulnerable to stressful conditions that lead to protein unfolding, a potential contributor to the retinal degeneration observed in this syndrome.
| S-EPMC4498062 | biostudies-literature
Project description:PurposeLeber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy, and invariably leads to blindness. LCA is a genetically and clinically heterogenous disorder. Although more than nine genes have been found to be associated with LCA, they only account for about half of LCA cases. We performed a comprehensive mutational analysis on nine known genes in 20 unrelated patients to investigate the genetic cause of LCA in Koreans.MethodsAll exons and flanking regions of the nine genes (AIPL1, CRB1, CRX, GUCY2D, RDH12, RPE65, RPGRIP1, LRAT, and TULP1) were analyzed by direct sequencing. We also screened our patients for the common CEP290: c.2991+1655A>G mutation found in Caucasian.ResultsSix different mutations including four novel ones were identified in three patients (15.0%): one frameshift, one nonsense, one splicing, and three missense mutations. These patients were compound heterozygotes and harbored two different mutations in CRB1, RPE65, and RPGRIP1, respectively. We identified three novel unclassified missense variants in RPGRIP1 of the three patients. These patients were heterozygous for each variant and did not have a large deletion or duplication in the same gene.ConclusionsThis comprehensive mutational analysis shows marked genetic heterogeneity in Korean LCA patients and reveals a mutation spectrum that differs from those previously reported. In turn, this suggests that a different strategy should be used for the molecular diagnosis of LCA in Koreans.
| S-EPMC2493025 | biostudies-literature
Project description:PurposeTo determine the therapeutic window for gene augmentation for Leber congenital amaurosis (LCA) associated with mutations in LCA5.MethodsFive patients (ages 6-31) with LCA and biallelic LCA5 mutations underwent an ophthalmic examination including optical coherence tomography (SD-OCT), full-field stimulus testing (FST), and pupillometry. The time course of photoreceptor degeneration in the Lca5gt/gt mouse model and the efficacy of subretinal gene augmentation therapy with AAV8-hLCA5 delivered at postnatal day 5 (P5) (early, n = 11 eyes), P15 (mid, n = 14), and P30 (late, n = 13) were assessed using SD-OCT, histologic study, electroretinography (ERG), and pupillometry. Comparisons were made with the human disease.ResultsPatients with LCA5-LCA showed a maculopathy with detectable outer nuclear layer (ONL) in the pericentral retina and at least 4 log units of dark-adapted sensitivity loss. The Lca5gt/gt mouse has a similarly severe and rapid photoreceptor degeneration. The ONL became progressively thinner and was undetectable by P60. Rod- and cone-mediated ERGs were severely reduced in amplitudes at P30 and became nondetectable by P60. Subretinal AAV8-hLCA5 administered to Lca5gt/gt mice at P5 and P15, but not at P30, resulted in structural and functional rescue.ConclusionsLCA5-LCA is a particularly severe form of LCA that was recapitulated in the Lca5gt/gt mouse. Gene augmentation resulted in structural and functional rescue in the Lca5gt/gt mouse if delivered before P30. Retained photoreceptors were visible within the central retina in all patients with LCA5-LCA, at a level equivalent to that observed in rescued Lca5gt/gt mice, suggesting a window of opportunity for the treatment of patients with LCA5-LCA.
| S-EPMC7405811 | biostudies-literature