Evaluation of Italian Patients with Leber Congenital Amaurosis due to AIPL1 Mutations Highlights the Potential Applicability of Gene Therapy

Testa, Francesco; Surace, Enrico Maria; Rossi, Silvia; Marrocco, Elena; Gargiulo, Annagiusi; Iorio, Valentina Di; Ziviello, Carmela; Nesti, Anna; Fecarotta, Simona; Bacci, Maria Laura; Giunti, Massimo; Corte, Michele Della; Banfi, Sandro; Auricchio, Alberto; Simonelli, Francesca

doi:10.1167/iovs.10-6543

Cited by 41 publications

(41 citation statements)

References 38 publications

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“…For both AIPL1 and GUCY2D, proof-of-concept studies in animal models have shown beneficial effects of subretinal delivery of adeno-associated vectors containing the wild-type coding sequence. [42][43][44] The young age of these patients (10, 2, and 5 years) and the knowledge of their molecular defect identified them as potentially eligible for future gene therapy trials.…”

Section: Discussionmentioning

confidence: 99%

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Coppieters

Wilde

Lefever

et al. 2012

Genetics in Medicine

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Purpose: Leber congenital amaurosis (LCA) is a rare congenital retinal dystrophy associated with 16 genes. Recent breakthroughs in LCA gene therapy offer the first prospect of treating inherited blindness, which requires an unequivocal and early molecular diagnosis. While present genetic tests do not address this due to a tremendous genetic heterogeneity, massively parallel sequencing (MPS) strategies might bring a solution. Here, we developed a comprehensive molecular test for LCA based on targeted MPS of all exons of 16 known LCA genes. methods:We designed a unique and flexible workflow for targeted resequencing of all 236 exons from 16 LCA genes based on quantitative PCR (qPCR) amplicon ligation, shearing, and parallel sequencing of multiple patients on a single lane of a short-read sequencer. Twenty-two prescreened LCA patients were included, five of whom had a known molecular cause.Results: Validation of 107 variations was performed as proof of concept. In addition, the causal genetic defect and a single heterozygous mutation were identified in 3 and 5, respectively, of 17 patients without previously identified mutations. conclusion:We propose a novel targeted MPS-based approach that is suitable for accurate, fast, and cost-effective early molecular testing in LCA, and easily applicable in other genetic disorders.Genet Med 2012:14(6):576-585

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Section: Discussionmentioning

confidence: 99%

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Coppieters

Wilde

Lefever

et al. 2012

Genetics in Medicine

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“…Indeed, the demand for RPE65 is likely higher in humans than in dogs. 54 Another potential culprit for the transient effects is related to the stage of the retina at the time of intervention and progressive loss of trophic support (especially regarding the cones). The study by Jacobson and colleagues 52 speculated that healthier photoreceptors survived in the treated retina, whereas other, more stressed rods were already in a preapoptotic state (''at the point of no return'') and continued to die.…”

Section: Gene Delivery: Viruses Nanoparticles Physical Methodsmentioning

confidence: 99%

“…62 A high level of AIPL1 photoreceptor expression and no toxicity were documented in Aipl1 null mice and porcine eyes that received subretinal administration of AAV2/8-AIPL1. 54 As some patients with AIPL1-associated disease have a late onset and slow progression rate, it may be a good candidate for gene augmentation therapy. 63 …”

Section: Implementation Of Gene Therapy For Other Inherited Retinal Dmentioning

confidence: 99%

Let There Be Light: Gene and Cell Therapy for Blindness

et al. 2016

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“…The most common LCA-causing mutation in the Caucasian population (CEP290, c.2991þ1655A.G), is responsible for 15% of all cases (den Hollander et al 2006;Perrault et al 2007;Coppieters et al 2010). In addition, the AIPL1 variant p.W278 Ã in exon 6, the GUCY2D p.R768W variant in exon 12, as well as CRB1 variants in exons 7 and 9 together explain another 20% of LCA alleles Testa et al 2011;Bujakowska et al 2012). Sequence analysis of these four exons is therefore proposed by the authors as a second prescreening step in LCA.…”

Section: Genomic Approaches For Heterogeneous Monogenic Diseasesmentioning

confidence: 99%

Genomic Approaches For the Discovery of Genes Mutated in Inherited Retinal Degeneration

Siemiątkowska

Collin

Hollander

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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Correspondence: Frans. Cremers@radboudumc.nl In view of their high degree of genetic heterogeneity, inherited retinal diseases (IRDs) pose a significant challenge for identifying novel genetic causes. Thus far, more than 200 genes have been found to be mutated in IRDs, which together contain causal variants in .80% of the cases. Accurate genetic diagnostics is particularly important for isolated cases, in which Xlinked and de novo autosomal dominant variants are not uncommon. In addition, new geneor mutation-specific therapies are emerging, underlining the importance of identifying causative mutations in each individual. Sanger sequencing of selected genes followed by costeffective targeted next-generation sequencing (NGS) can identify defects in known IRDassociated genes in the majority of the cases. Exome NGS in combination with genetic linkage or homozygosity mapping studies can aid the identification of the remaining causal genes. As these are thought to be mutated in ,1% of the cases, validation through functional modeling in, for example, zebrafish and/or replication through the genotyping of large patient cohorts is required. In the near future, whole genome NGS in combination with transcriptome NGS may reveal mutations that are currently hidden in the noncoding regions of the human genome.

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Evaluation of Italian Patients with Leber Congenital Amaurosis due to AIPL1 Mutations Highlights the Potential Applicability of Gene Therapy

Cited by 41 publications

References 38 publications

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Massively parallel sequencing for early molecular diagnosis in Leber congenital amaurosis

Let There Be Light: Gene and Cell Therapy for Blindness

Genomic Approaches For the Discovery of Genes Mutated in Inherited Retinal Degeneration

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