Author
Bart P. Leroy
Other affiliations: Ghent University Hospital, Ghent University
Bio: Bart P. Leroy is an academic researcher from Children's Hospital of Philadelphia. The author has contributed to research in topics: Retinitis pigmentosa & Visual acuity. The author has an hindex of 40, co-authored 139 publications receiving 6460 citations. Previous affiliations of Bart P. Leroy include Ghent University Hospital & Ghent University.
Papers published on a yearly basis
Papers
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TL;DR: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable.
1,081 citations
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TL;DR: The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain.
793 citations
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TL;DR: To the knowledge, AAV2-hRPE65v2 is the first successful gene therapy administered to the contralateral eye and the results highlight the use of several outcome measures and help to delineate the variables that contribute to maximal benefit from gene augmentation therapy in this disease.
351 citations
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TL;DR: The purpose of this review is to describe this spectrum of phenotypes, which includes Best vitelliform macular dystrophy and adult-onset foveomacular viteLLiform Dystrophy, autosomal dominant vitreoretinochoroidopathy, the MRCS (microcornea, rod-cone dystrohy, cataract, posterior staphyloma) syndrome, and autosomal recessive bestrophinopathy.
286 citations
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TL;DR: A distinct retinal disorder, autosomal-recessive bestrophinopathy (ARB), that is consequent upon biallelic mutation in BEST1 and is associated with central visual loss, a characteristic retinopathy, an absent electro-oculogram light rise, and a reduced electroretinogram is described.
Abstract: We describe a distinct retinal disorder, autosomal-recessive bestrophinopathy (ARB), that is consequent upon biallelic mutation in BEST1 and is associated with central visual loss, a characteristic retinopathy, an absent electro-oculogram light rise, and a reduced electroretinogram. Heterozygous mutations in BEST1 have previously been found to cause the two dominantly inherited disorders, Best macular dystrophy and autosomal-dominant vitreoretinochoroidopathy. The transmembrane protein bestrophin-1, encoded by BEST1, is located at the basolateral membrane of the retinal pigment epithelium in which it probably functions as a Cl− channel. We sequenced BEST1 in five families, identifying DNA variants in each of ten alleles. These encoded six different missense variants and one nonsense variant. The alleles segregated appropriately for a recessive disorder in each family. No clinical or electrophysiological abnormalities were identified in any heterozygotes. We conducted whole-cell patch-clamping of HEK293 cells transfected with bestrophin-1 to measure the Cl− current. Two ARB missense isoforms severely reduced channel activity. However, unlike two other alleles previously associated with Best disease, cotransfection with wild-type bestrophin-1 did not impair the formation of active wild-type bestrophin-1 channels, consistent with the recessive nature of the condition. We propose that ARB is the null phenotype of bestrophin-1 in humans.
262 citations
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TL;DR: It is suggested that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is involved in the developmental process that culminates in speech and language.
Abstract: Individuals affected with developmental disorders of speech and language have substantial difficulty acquiring expressive and/or receptive language in the absence of any profound sensory or neurological impairment and despite adequate intelligence and opportunity. Although studies of twins consistently indicate that a significant genetic component is involved, most families segregating speech and language deficits show complex patterns of inheritance, and a gene that predisposes individuals to such disorders has not been identified. We have studied a unique three-generation pedigree, KE, in which a severe speech and language disorder is transmitted as an autosomal-dominant monogenic trait. Our previous work mapped the locus responsible, SPCH1, to a 5.6-cM interval of region 7q31 on chromosome 7 (ref. 5). We also identified an unrelated individual, CS, in whom speech and language impairment is associated with a chromosomal translocation involving the SPCH1 interval. Here we show that the gene FOXP2, which encodes a putative transcription factor containing a polyglutamine tract and a forkhead DNA-binding domain, is directly disrupted by the translocation breakpoint in CS. In addition, we identify a point mutation in affected members of the KE family that alters an invariant amino-acid residue in the forkhead domain. Our findings suggest that FOXP2 is involved in the developmental process that culminates in speech and language.
1,815 citations
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TL;DR: This work presents a method for prioritization of candidate genes by use of a global network distance measure, random walk analysis, for definition of similarities in protein-protein interaction networks, significantly outperforming previous methods based on local distance measures.
Abstract: The identification of genes associated with hereditary disorders has contributed to improving medical care and to a better understanding of gene functions, interactions, and pathways. However, there are well over 1500 Mendelian disorders whose molecular basis remains unknown. At present, methods such as linkage analysis can identify the chromosomal region in which unknown disease genes are located, but the regions could contain up to hundreds of candidate genes. In this work, we present a method for prioritization of candidate genes by use of a global network distance measure, random walk analysis, for definition of similarities in protein-protein interaction networks. We tested our method on 110 disease-gene families with a total of 783 genes and achieved an area under the ROC curve of up to 98% on simulated linkage intervals of 100 genes surrounding the disease gene, significantly outperforming previous methods based on local distance measures. Our results not only provide an improved tool for positional-cloning projects but also add weight to the assumption that phenotypically similar diseases are associated with disturbances of subnetworks within the larger protein interactome that extend beyond the disease proteins themselves.
1,135 citations
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TL;DR: Voretigene neparvovec gene replacement improved functional vision in RPE65-mediated inherited retinal dystrophy previously medically untreatable.
1,081 citations
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TL;DR: The fundamentals of AAV and vectorology are discussed, focusing on current therapeutic strategies, clinical progress and ongoing challenges.
Abstract: Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Recent advances in developing clinically desirable AAV capsids, optimizing genome designs and harnessing revolutionary biotechnologies have contributed substantially to the growth of the gene therapy field. Preclinical and clinical successes in AAV-mediated gene replacement, gene silencing and gene editing have helped AAV gain popularity as the ideal therapeutic vector, with two AAV-based therapeutics gaining regulatory approval in Europe or the United States. Continued study of AAV biology and increased understanding of the associated therapeutic challenges and limitations will build the foundation for future clinical success.
1,041 citations
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TL;DR: Investigating ciliopathies has helped to understand the molecular mechanisms by which the cilium-associated basal body functions in early ciliogenesis, as well as how the transition zone functions in ciliary gating, and how intraflagellar transport enables cargo trafficking and signalling.
Abstract: Motile and non-motile (primary) cilia are nearly ubiquitous cellular organelles. The dysfunction of cilia causes diseases known as ciliopathies. The number of reported ciliopathies (currently 35) is increasing, as is the number of established (187) and candidate (241) ciliopathy-associated genes. The characterization of ciliopathy-associated proteins and phenotypes has improved our knowledge of ciliary functions. In particular, investigating ciliopathies has helped us to understand the molecular mechanisms by which the cilium-associated basal body functions in early ciliogenesis, as well as how the transition zone functions in ciliary gating, and how intraflagellar transport enables cargo trafficking and signalling. Both basic biological and clinical studies are uncovering novel ciliopathies and the ciliary proteins involved. The assignment of these proteins to different ciliary structures, processes and ciliopathy subclasses (first order and second order) provides insights into how this versatile organelle is built, compartmentalized and functions in diverse ways that are essential for human health.
1,017 citations