gms | German Medical Science

26. Jahrestagung der Deutschen Retinologischen Gesellschaft

Deutsche Gesellschaft für Retinologie

27.09.2013, Hamburg

Methods in Genetics in inherited retinal disorders and Gene therapy trials

Meeting Abstract

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  • Christina Zeitz - INSERM, UMR_S968, Paris, France; CNRS, UMR_7210, Paris, France; UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
  • S. El Shamieh - INSERM, UMR_S968, Paris, France; CNRS, UMR_7210, Paris, France; UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France
  • I. Audo - INSERM, UMR_S968, Paris, France; CNRS, UMR_7210, Paris, France; UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France; Institute of Ophthalmology, University College of London, London, UK
  • J.-A. Sahel - INSERM, UMR_S968, Paris, France; CNRS, UMR_7210, Paris, France; UPMC Univ Paris 06, UMR_S 968, Institut de la Vision, Paris, France; Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS CIC 503, Paris, France; Institute of Ophthalmology, University College of London, London, UK; Fondation Ophtalmologique Adolphe de Rothschild, Paris, France; Académie des Sciences-Institut de France, Paris, France

Retinologische Gesellschaft. 26. Jahrestagung der Retinologischen Gesellschaft. Hamburg, 27.-27.09.2013. Düsseldorf: German Medical Science GMS Publishing House; 2013. Doc13rg12

doi: 10.3205/13rg12, urn:nbn:de:0183-13rg126

Veröffentlicht: 20. August 2013

© 2013 Zeitz et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielfältigt, verbreitet und öffentlich zugänglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

Text

Inherited retinal disorders (IRD) are clinically and genetically heterogeneous with more than 150 gene defects accounting for the diversity of disease phenotypes. Over the past two decades, three main approaches including Sanger sequencing, arrayed primer extension (APEX) chip technology and homozygosity mapping were used to investigate the genetics of IRD. Despite many advantages, the above-mentioned technologies have numerous limitations, an example of such limitation is the diagnostic value provided by APEX that remained low (10%–20%) for rod-cone dystrophy patients. Applying Sanger sequencing to IRD patients resulted in a higher detection rate, however analyzing hundreds of exons across the genome is an enormous effort in terms of time and cost. Homozygosity mapping is also considered as a powerful tool in identifying novel and known gene defects, but such an approach is only successful when applied to consanguineous families or inbred populations. With the emergence of novel sequencing techniques (targeted and whole exome), great efforts are currently conducted in order to report novel gene defects implicated in the aetiology of human diseases. This technology has provided accurate qualitative and quantitative information about any type of nucleic acid in a given sample at a high-throughput while incurring relatively limited costs. We have previously developed, in collaboration with a company (Integragen, France) an unbiased and time-efficient retinal gene array for next generation sequencing (NGS), which targets in total 254 genes. Subsequently, we have validated and then enhanced our NGS retinal panel by improving the coverage of target genomic regions and restricting it to the most relevant genes underlying progressive inherited retinal disorders, thus reducing the number of targeted genes to 121. Herein we present different filtering approaches that we apply to identify the genetic defects and their prevalence in our cohort. Subsequent Sanger sequencing, co-segregation analysis and re-investigation of the phenotype to validate the gene defects are crucial to prepare patients for gene therapy approaches. During the last decade, gene replacement therapies achieved significant success not only in animal models of retinal degeneration, but also in humans. Pioneering clinical studies are now under way to evaluate their safety and efficacy in inherited monogenic eye diseases. Thus we intend to give an update of ongoing gene therapy trials for Leber Congenital Amaurosis, Stargardt disease, Choroideremia Usher syndrome and rod-cone dystrophy.