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size="30" maxlength="200" value="91100" /></form> </div> </div> </div> </div> </header> <div id="Subheader" style=""><div class="container"><div class="column one"><h1 class="title">Research Projects</h1></div></div></div> </div>  <div id="Content" role="main"> <div class="content_wrapper clearfix"> <div class="sections_group"> <div class="entry-content" itemprop="mainContentOfPage"> <div class="mfn-builder-content mfn-default-content-buider"><div class="section mcb-section mfn-default-section mcb-section-110344f0b" style="" ><div class="mcb-background-overlay"></div><div class="section_wrapper mcb-section-inner mcb-section-inner-110344f0b"><div class="wrap mcb-wrap mcb-wrap-7d5bc79c9 one tablet-one mobile-one valign-top clearfix" data-desktop-col="one" data-tablet-col="tablet-one" data-mobile-col="mobile-one" style="padding:;background-color:" ><div class="mcb-wrap-inner mcb-wrap-inner-7d5bc79c9" ><div class="mcb-wrap-background-overlay"></div><div class="column mcb-column mcb-item-48df3a333 one tablet-one mobile-one column_column" style="" ><div class="mcb-column-inner mcb-column-inner-48df3a333 mcb-item-column-inner"><div class="column_attr mfn-inline-editor clearfix" style=""><h2 class="blue">The Curing Retinal Blindness Foundation is pleased to be funding the following research projects:</h4> <p><span class="blue">Mutated CRB1 in human induced pluripotent stem cell derived retinal organoids</span></p> <p>Eberhard Karls University Tuebingen</p> <p>Institute of Neuroanatomy</p> <p>Stefan Liebau & Marius Ueffing</p> <hr> <p><span class="blue">Establishing 3-Dimensional (3D) Retinal Optic Cups using patient-specific CRB1 Induced Pluripotent Stem Cells</span></p> <p>University of Pennsylvania Perelman School of Medicine Jason A Mills, PhD</p> <p>Director of iPSC Core at the Center for Advanced Retinal and Ocular Therapeutics (CAROT)</p> <hr> <p><span class="blue">Retinal dystrophies associated with mutations in the CRB1 gene: towards gene therapy</span></p> <p>Leiden University Medical Centre, the Netherlands</p> <p>Camiel J.F. Boon, MD, PhD, FEBOphth</p> </div></div></div></div></div></div></div><div class="section mcb-section mfn-default-section mcb-section-426142955 full-width full-width-deprecated" style="" ><div class="mcb-background-overlay"></div><div class="section_wrapper mcb-section-inner mcb-section-inner-426142955"><div class="wrap mcb-wrap mcb-wrap-9db641e16 one tablet-one mobile-one valign-top bg-cover clearfix" data-desktop-col="one" data-tablet-col="tablet-one" data-mobile-col="mobile-one" style="padding:;background-color:" ><div class="mcb-wrap-inner mcb-wrap-inner-9db641e16" ><div class="mcb-wrap-background-overlay"></div><div class="column mcb-column mcb-item-ec5ec6608 one tablet-one mobile-one column_column" style="" ><div class="mcb-column-inner mcb-column-inner-ec5ec6608 mcb-item-column-inner"><div class="column_attr mfn-inline-editor clearfix lazyload" style="background-repeat:no-repeat;background-position:center top;padding:15px 0px 0px 0px;" data-back="https://crb1.org/wp-content/uploads/2020/05/blue-line-divider-1920w.png"></div></div></div></div></div></div></div><div class="section mcb-section mfn-default-section mcb-section-e32126868 nMargin" style="padding-top:40px;background-color:rgba(0, 0, 0, .01)" ><div class="mcb-background-overlay"></div><div class="section_wrapper mcb-section-inner mcb-section-inner-e32126868"><div class="wrap mcb-wrap mcb-wrap-6eb5631b9 one tablet-one mobile-one valign-top clearfix" data-desktop-col="one" data-tablet-col="tablet-one" data-mobile-col="mobile-one" style="padding:;background-color:" ><div class="mcb-wrap-inner mcb-wrap-inner-6eb5631b9" ><div class="mcb-wrap-background-overlay"></div><div class="column mcb-column mcb-item-06edf3648 one-second tablet-one-second mobile-one column_photo_box" style="" ><div class="mcb-column-inner mcb-column-inner-06edf3648 mcb-item-photo_box-inner"><div class="photo_box element_classes without-desc"><div class="image_frame"><div class="image_wrapper"><div class="mask"></div><img class="scale-with-grid lazyload" src="data:image/gif;base64,R0lGODlhAQABAAAAACH5BAEKAAEALAAAAAABAAEAAAICTAEAOw==" alt="Research Projects" width="" height="" data-src="https://crb1.org/wp-content/uploads/2020/11/Photo-Nov-01-4-41-54-PM-scaled.jpg" decoding="async" /><noscript><img class="scale-with-grid" src="https://crb1.org/wp-content/uploads/2020/11/Photo-Nov-01-4-41-54-PM-scaled.jpg" alt="Research Projects" width="" height="" data-eio="l" /></noscript></div></div></div> </div></div><div class="column mcb-column mcb-item-7a0d42b82 one-second tablet-one-second mobile-one column_photo_box" style="" ><div class="mcb-column-inner mcb-column-inner-7a0d42b82 mcb-item-photo_box-inner"><div class="photo_box element_classes without-desc"><div class="image_frame"><div class="image_wrapper"><div class="mask"></div><img class="scale-with-grid lazyload" src="data:image/gif;base64,R0lGODlhAQABAAAAACH5BAEKAAEALAAAAAABAAEAAAICTAEAOw==" alt="Research Projects" width="" height="" data-src="https://crb1.org/wp-content/uploads/2020/11/IMG_5169-scaled.jpg" decoding="async" /><noscript><img class="scale-with-grid" src="https://crb1.org/wp-content/uploads/2020/11/IMG_5169-scaled.jpg" alt="Research Projects" width="" height="" data-eio="l" /></noscript></div></div></div> </div></div><div class="column mcb-column mcb-item-d82155fac one tablet-one mobile-one column_column" style="" ><div class="mcb-column-inner mcb-column-inner-d82155fac mcb-item-column-inner"><div class="column_attr mfn-inline-editor clearfix" style=""><p>Mutations in the CRB1 gene are a relatively frequent cause of Leber congenital amaurosis (LCA) and autosomal recessive retinitis pigmentosa (RP). The first human gene therapy trial for patients with retinal dystrophy caused by CRB1 gene mutations is currently being prepared at Leiden University Medical Center (LUMC) in the Netherlands. However, surprisingly little is known about the clinical characteristics and the prognosis of patients with CRB1 mutations. Such information is very important not only to be able to better inform patients about the disease prognosis, but also for better selection of patients for future gene therapy. This current knowledge is limited due to inconsistent results between previous studies and relatively small patient groups. Our study aims to analyze the clinical characteristics and natural disease course of these patients, and to analyze possible correlations between the specific CRB1 gene defects and the clinical characteristics (genotype-phenotype correlations). Also, we will take questionnaires assessing vision-related quality of life and social participation to better assess the impact of the disease for the individual patient. Collaboration with other Dutch medical centers and rehabilitation institutes will lead to a large patient cohort.</p></div></div></div></div></div></div></div><div class="section mcb-section mfn-default-section mcb-section-e3ebeec13" style="padding-top:40px;background-color:#034ea2" ><div class="mcb-background-overlay"></div><div class="section_wrapper mcb-section-inner mcb-section-inner-e3ebeec13"><div class="wrap mcb-wrap mcb-wrap-e3ea9deda one tablet-one mobile-one valign-top clearfix" data-desktop-col="one" data-tablet-col="tablet-one" data-mobile-col="mobile-one" style="padding:;background-color:" ><div class="mcb-wrap-inner mcb-wrap-inner-e3ea9deda" ><div class="mcb-wrap-background-overlay"></div><div class="column mcb-column mcb-item-a085096ee one tablet-one mobile-one column_column" style="" ><div class="mcb-column-inner mcb-column-inner-a085096ee mcb-item-column-inner"><div class="column_attr mfn-inline-editor clearfix" style=""><h4 class="white">Deep sequencing CRB1 Leber Congenital Amaurosis mouse retinas Netherlands Institute for Neuroscience Jan Wijnholds, PhD</h4> <p class="white">The Wijnholds’ team made significant progress in developing gene therapy against blindness due to mutations in the CRB1 gene. The project nearly finished its pre-clinical phase showing efficacy of newly developed gene therapy vectors in mice, and is preparing for the pharmaceutical phase in which a gene therapy vector for clinical use is prepared and tested for quality. The researchers believe that the vector is most promising for retinitis pigmentosa due to mutations in the CRB1 gene, but are examining its potential use for Leber congenital amaurosis as well.</p></div></div></div><div class="column mcb-column mcb-item-edac92545 one tablet-one mobile-one column_column" style="" ><div class="mcb-column-inner mcb-column-inner-edac92545 mcb-item-column-inner"><div class="column_attr mfn-inline-editor clearfix" style=""><h4 class="white">Modifier Genes of Retinal Pathology in Crb1rd8 Mice The Jackson Laboratory, USA Mark P Krebs, PhD</h4> <p class="white">We will use a mouse Crb1 mutant strain to identify modifier genes that cause variation in the severity of CRB1-associated retinal disease. Identifying modifier genes will help us understand how CRB1 mutations cause blindness and may provide new targets for therapeutic intervention.</p></div></div></div><div class="column mcb-column mcb-item-1be3e3a20 one tablet-one mobile-one column_column" style="" ><div class="mcb-column-inner mcb-column-inner-1be3e3a20 mcb-item-column-inner"><div class="column_attr mfn-inline-editor clearfix" style=""><h4 class="white">Collection of all CRB1-associated mutations in a publicly accessible database Radboud University Medical Center, Nijmegen, The Netherlands Frans P.M. Cremers, PhD</h4> <p class="white">In the last two decades, approximately 80% of the genes underlying inherited retinal degeneration have been identified. Momentarily, more than 10.000 variants have been published for the 100 genes implicated in inherited retinal diseases. We are however lacking a comprehensive and publicly accessible mutation database to register these variants. Such a database is important to keep up-to-date with all patients for which causative mutations have been identified, which will form the basis to understand which DNA variants are causing disease and to select patients for novel therapies. Together with my collaborator, prof. R. Qamar (Islamabad), I have embarked on an ambitious programme which aims at the collection of all DNA variants associated with inherited retinal diseases and to collect information on their prevalence by registering each individual patient in gene-specific databases. In this project, financed by the Curing Retinal Blindness Foundation, we will collect CRB1 mutation data of all published cases with congenital blindness or retinitis pigmentosa.</p></div></div></div><div class="column mcb-column mcb-item-edbf02040 one tablet-one mobile-one column_column" style="" ><div class="mcb-column-inner mcb-column-inner-edbf02040 mcb-item-column-inner"><div class="column_attr mfn-inline-editor clearfix" style=""><h4 class="white">Construction of Adeno-associated viral vector for human Crb1 gene therapy Temple University School of Medicine/Shriners Hospitals, USA Seo-Hee Cho, PhD</h4> <p class="white">One of the main difficulties in gene therapy for LCA8 is the production of an effective viral vector which can deliver normal copies of the Crb1 gene to the retinal cells in which the gene is mutated. Although the conventional recombinant adeno-associated virus (rAAV) system provides critical advantages, a major constraint is the limitation in the size of the gene that can be packaged into the viral genome. Due to the large size of the Crb1 gene, it is not feasible to produce an effective, high-titer virus using the traditional promoter system. In order to overcome this size limitation constraint, we will employ recombinant DNA technology to construct novel rAAV vectors with minimal promoter elements to drive the expression of Crb1. We will then assess the level of Crb1 expression and the extent of cellular infectivity attained by these novel vectors.</p></div></div></div><div class="column mcb-column mcb-item-ec8897d99 one tablet-one mobile-one column_column" style="" ><div class="mcb-column-inner mcb-column-inner-ec8897d99 mcb-item-column-inner"><div class="column_attr mfn-inline-editor clearfix" style=""><h4 class="white">Identification of persons with congenital blindness or retinitis pigmentosa and CRB1 variants by sequence analysis of 4.000 European and North-American patients Radboud University Medical Center, Nijmegen, The Netherlands Frans P.M. Cremers, PhD</h4> <p class="white">The scientific community has identified ~80% of the genes underlying inherited retinal degeneration (IRD). Recently, large-scale DNA sequencing technologies have facilitated the identification of novel IRD genes, but they were not designed for the cost-effective sequence analysis of individual genes in large groups of patients. The identification of all patients with CRB1 mutations is crucial to create awareness of the importance of this retinal disease subtype in view of necessary investments to develop gene-therapy, and to increase the number of patients that are eligible for novel treatments. In a EU-funded study we investigated the prevalence of CRB1 variants in a cohort of Dutch and German persons with retinitis pigmentosa or congenital blindness. We found CRB1 variants in 35 of 820 patients, which is 3 times higher than expected based on previous publications. In this project, we propose to expand this study by systematically testing 4000 cases with retinitis pigmentosa or congenital blindness from Europe and North-America for mutations in the CRB1 gene and 100 other IRD genes, using a cost-effective novel sequencing method. The grant from the Curing Retinal Blindness Foundation will enable us to analyse 400 cases for variants in CRB1 and other IRD genes, and we expect to find ~120 probands with CRB1 variants in the total group of 4000 patients. This would effectively double the number of CRB1-associated families worldwide.</p></div></div></div></div></div></div></div><div class="section mcb-section mfn-default-section mcb-section-3c733ed40" style="padding-top:40px" ><div class="mcb-background-overlay"></div><div class="section_wrapper mcb-section-inner mcb-section-inner-3c733ed40"><div class="wrap mcb-wrap mcb-wrap-2d1e16b20 one tablet-one mobile-one valign-top clearfix" data-desktop-col="one" data-tablet-col="tablet-one" data-mobile-col="mobile-one" style="padding:;background-color:" ><div class="mcb-wrap-inner mcb-wrap-inner-2d1e16b20" ><div class="mcb-wrap-background-overlay"></div><div class="column mcb-column mcb-item-7ea04fddd one tablet-one mobile-one column_column" style="" ><div class="mcb-column-inner mcb-column-inner-7ea04fddd mcb-item-column-inner"><div class="column_attr mfn-inline-editor clearfix align_center" style=""><h2>To get in touch use the link below.</h2> <a href="/contact" class="yellowbutton">Contact</a></div></div></div></div></div></div></div></div><div class="section the_content no_content"><div class="section_wrapper"><div class="the_content_wrapper "></div></div></div> <div class="section section-page-footer"> <div class="section_wrapper clearfix"> <div class="column one page-pager"> <div class="mcb-column-inner"> </div> </div> </div> </div> </div> </div> </div> </div>   <footer id="Footer" class="clearfix"> <div class="widgets_wrapper" style=""><div class="container"><div class="column one-fourth"><aside id="media_image-3" class="widget widget_media_image"><img width="300" height="204" src="data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAASwAAADMAQMAAADzgAwAAAAABlBMVEUAAAD///+l2Z/dAAAAAXRSTlMAQObYZgAAAAlwSFlzAAAOxAAADsQBlSsOGwAAAB5JREFUWMPtwQENAAAAwqD3T20PBxQAAAAAAAAAfBofFAAB9ISzJwAAAABJRU5ErkJggg==" class="image wp-image-232 attachment-medium size-medium lazyload" alt="" style="max-width: 100%; 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85.75c5.75 5.75 9.25 14 9.25 22.5z"></path></svg></span><span class="pojo-a11y-toolbar-text">Decrease Text</span> </a> </li> <li class="pojo-a11y-toolbar-item"> <a href="#" class="pojo-a11y-toolbar-link pojo-a11y-btn-background-group pojo-a11y-btn-grayscale" data-action="grayscale" data-action-group="schema" tabindex="-1" role="button"> <span class="pojo-a11y-toolbar-icon"><svg version="1.1" xmlns="http://www.w3.org/2000/svg" width="1em" viewBox="0 0 448 448"><title>Grayscale</title><path fill="currentColor" d="M15.75 384h-15.75v-352h15.75v352zM31.5 383.75h-8v-351.75h8v351.75zM55 383.75h-7.75v-351.75h7.75v351.75zM94.25 383.75h-7.75v-351.75h7.75v351.75zM133.5 383.75h-15.5v-351.75h15.5v351.75zM165 383.75h-7.75v-351.75h7.75v351.75zM180.75 383.75h-7.75v-351.75h7.75v351.75zM196.5 383.75h-7.75v-351.75h7.75v351.75zM235.75 383.75h-15.75v-351.75h15.75v351.75zM275 383.75h-15.75v-351.75h15.75v351.75zM306.5 383.75h-15.75v-351.75h15.75v351.75zM338 383.75h-15.75v-351.75h15.75v351.75zM361.5 383.75h-15.75v-351.75h15.75v351.75zM408.75 383.75h-23.5v-351.75h23.5v351.75zM424.5 383.75h-8v-351.75h8v351.75zM448 384h-15.75v-352h15.75v352z"></path></svg></span><span class="pojo-a11y-toolbar-text">Grayscale</span> </a> </li> <li class="pojo-a11y-toolbar-item"> <a href="#" class="pojo-a11y-toolbar-link pojo-a11y-btn-background-group pojo-a11y-btn-high-contrast" data-action="high-contrast" data-action-group="schema" tabindex="-1" role="button"> <span class="pojo-a11y-toolbar-icon"><svg version="1.1" xmlns="http://www.w3.org/2000/svg" width="1em" viewBox="0 0 448 448"><title>High Contrast</title><path fill="currentColor" d="M192 360v-272c-75 0-136 61-136 136s61 136 136 136zM384 224c0 106-86 192-192 192s-192-86-192-192 86-192 192-192 192 86 192 192z"></path></svg></span><span class="pojo-a11y-toolbar-text">High Contrast</span> </a> </li> <li class="pojo-a11y-toolbar-item"> <a href="#" class="pojo-a11y-toolbar-link pojo-a11y-btn-background-group pojo-a11y-btn-negative-contrast" data-action="negative-contrast" data-action-group="schema" tabindex="-1" role="button"> <span class="pojo-a11y-toolbar-icon"><svg version="1.1" xmlns="http://www.w3.org/2000/svg" width="1em" viewBox="0 0 448 448"><title>Negative Contrast</title><path fill="currentColor" d="M416 240c-23.75-36.75-56.25-68.25-95.25-88.25 10 17 15.25 36.5 15.25 56.25 0 61.75-50.25 112-112 112s-112-50.25-112-112c0-19.75 5.25-39.25 15.25-56.25-39 20-71.5 51.5-95.25 88.25 42.75 66 111.75 112 192 112s149.25-46 192-112zM236 144c0-6.5-5.5-12-12-12-41.75 0-76 34.25-76 76 0 6.5 5.5 12 12 12s12-5.5 12-12c0-28.5 23.5-52 52-52 6.5 0 12-5.5 12-12zM448 240c0 6.25-2 12-5 17.25-46 75.75-130.25 126.75-219 126.75s-173-51.25-219-126.75c-3-5.25-5-11-5-17.25s2-12 5-17.25c46-75.5 130.25-126.75 219-126.75s173 51.25 219 126.75c3 5.25 5 11 5 17.25z"></path></svg></span><span class="pojo-a11y-toolbar-text">Negative Contrast</span> </a> </li> <li class="pojo-a11y-toolbar-item"> <a href="#" class="pojo-a11y-toolbar-link pojo-a11y-btn-background-group pojo-a11y-btn-light-background" data-action="light-background" data-action-group="schema" tabindex="-1" role="button"> <span class="pojo-a11y-toolbar-icon"><svg version="1.1" xmlns="http://www.w3.org/2000/svg" width="1em" viewBox="0 0 448 448"><title>Light Background</title><path fill="currentColor" d="M184 144c0 4.25-3.75 8-8 8s-8-3.75-8-8c0-17.25-26.75-24-40-24-4.25 0-8-3.75-8-8s3.75-8 8-8c23.25 0 56 12.25 56 40zM224 144c0-50-50.75-80-96-80s-96 30-96 80c0 16 6.5 32.75 17 45 4.75 5.5 10.25 10.75 15.25 16.5 17.75 21.25 32.75 46.25 35.25 74.5h57c2.5-28.25 17.5-53.25 35.25-74.5 5-5.75 10.5-11 15.25-16.5 10.5-12.25 17-29 17-45zM256 144c0 25.75-8.5 48-25.75 67s-40 45.75-42 72.5c7.25 4.25 11.75 12.25 11.75 20.5 0 6-2.25 11.75-6.25 16 4 4.25 6.25 10 6.25 16 0 8.25-4.25 15.75-11.25 20.25 2 3.5 3.25 7.75 3.25 11.75 0 16.25-12.75 24-27.25 24-6.5 14.5-21 24-36.75 24s-30.25-9.5-36.75-24c-14.5 0-27.25-7.75-27.25-24 0-4 1.25-8.25 3.25-11.75-7-4.5-11.25-12-11.25-20.25 0-6 2.25-11.75 6.25-16-4-4.25-6.25-10-6.25-16 0-8.25 4.5-16.25 11.75-20.5-2-26.75-24.75-53.5-42-72.5s-25.75-41.25-25.75-67c0-68 64.75-112 128-112s128 44 128 112z"></path></svg></span><span class="pojo-a11y-toolbar-text">Light Background</span> </a> </li> <li class="pojo-a11y-toolbar-item"> <a href="#" class="pojo-a11y-toolbar-link pojo-a11y-btn-links-underline" data-action="links-underline" data-action-group="toggle" tabindex="-1" role="button"> <span class="pojo-a11y-toolbar-icon"><svg version="1.1" xmlns="http://www.w3.org/2000/svg" width="1em" viewBox="0 0 448 448"><title>Links Underline</title><path fill="currentColor" d="M364 304c0-6.5-2.5-12.5-7-17l-52-52c-4.5-4.5-10.75-7-17-7-7.25 0-13 2.75-18 8 8.25 8.25 18 15.25 18 28 0 13.25-10.75 24-24 24-12.75 0-19.75-9.75-28-18-5.25 5-8.25 10.75-8.25 18.25 0 6.25 2.5 12.5 7 17l51.5 51.75c4.5 4.5 10.75 6.75 17 6.75s12.5-2.25 17-6.5l36.75-36.5c4.5-4.5 7-10.5 7-16.75zM188.25 127.75c0-6.25-2.5-12.5-7-17l-51.5-51.75c-4.5-4.5-10.75-7-17-7s-12.5 2.5-17 6.75l-36.75 36.5c-4.5 4.5-7 10.5-7 16.75 0 6.5 2.5 12.5 7 17l52 52c4.5 4.5 10.75 6.75 17 6.75 7.25 0 13-2.5 18-7.75-8.25-8.25-18-15.25-18-28 0-13.25 10.75-24 24-24 12.75 0 19.75 9.75 28 18 5.25-5 8.25-10.75 8.25-18.25zM412 304c0 19-7.75 37.5-21.25 50.75l-36.75 36.5c-13.5 13.5-31.75 20.75-50.75 20.75-19.25 0-37.5-7.5-51-21.25l-51.5-51.75c-13.5-13.5-20.75-31.75-20.75-50.75 0-19.75 8-38.5 22-52.25l-22-22c-13.75 14-32.25 22-52 22-19 0-37.5-7.5-51-21l-52-52c-13.75-13.75-21-31.75-21-51 0-19 7.75-37.5 21.25-50.75l36.75-36.5c13.5-13.5 31.75-20.75 50.75-20.75 19.25 0 37.5 7.5 51 21.25l51.5 51.75c13.5 13.5 20.75 31.75 20.75 50.75 0 19.75-8 38.5-22 52.25l22 22c13.75-14 32.25-22 52-22 19 0 37.5 7.5 51 21l52 52c13.75 13.75 21 31.75 21 51z"></path></svg></span><span class="pojo-a11y-toolbar-text">Links Underline</span> </a> </li> <li class="pojo-a11y-toolbar-item"> <a href="#" class="pojo-a11y-toolbar-link pojo-a11y-btn-readable-font" data-action="readable-font" data-action-group="toggle" tabindex="-1" role="button"> <span class="pojo-a11y-toolbar-icon"><svg version="1.1" xmlns="http://www.w3.org/2000/svg" width="1em" viewBox="0 0 448 448"><title>Readable Font</title><path fill="currentColor" d="M181.25 139.75l-42.5 112.5c24.75 0.25 49.5 1 74.25 1 4.75 0 9.5-0.25 14.25-0.5-13-38-28.25-76.75-46-113zM0 416l0.5-19.75c23.5-7.25 49-2.25 59.5-29.25l59.25-154 70-181h32c1 1.75 2 3.5 2.75 5.25l51.25 120c18.75 44.25 36 89 55 133 11.25 26 20 52.75 32.5 78.25 1.75 4 5.25 11.5 8.75 14.25 8.25 6.5 31.25 8 43 12.5 0.75 4.75 1.5 9.5 1.5 14.25 0 2.25-0.25 4.25-0.25 6.5-31.75 0-63.5-4-95.25-4-32.75 0-65.5 2.75-98.25 3.75 0-6.5 0.25-13 1-19.5l32.75-7c6.75-1.5 20-3.25 20-12.5 0-9-32.25-83.25-36.25-93.5l-112.5-0.5c-6.5 14.5-31.75 80-31.75 89.5 0 19.25 36.75 20 51 22 0.25 4.75 0.25 9.5 0.25 14.5 0 2.25-0.25 4.5-0.5 6.75-29 0-58.25-5-87.25-5-3.5 0-8.5 1.5-12 2-15.75 2.75-31.25 3.5-47 3.5z"></path></svg></span><span class="pojo-a11y-toolbar-text">Readable Font</span> </a> </li> <li class="pojo-a11y-toolbar-item"> <a href="#" class="pojo-a11y-toolbar-link pojo-a11y-btn-reset" data-action="reset" tabindex="-1" role="button"> <span class="pojo-a11y-toolbar-icon"><svg version="1.1" xmlns="http://www.w3.org/2000/svg" width="1em" viewBox="0 0 448 448"><title>Reset</title><path fill="currentColor" d="M384 224c0 105.75-86.25 192-192 192-57.25 0-111.25-25.25-147.75-69.25-2.5-3.25-2.25-8 0.5-10.75l34.25-34.5c1.75-1.5 4-2.25 6.25-2.25 2.25 0.25 4.5 1.25 5.75 3 24.5 31.75 61.25 49.75 101 49.75 70.5 0 128-57.5 128-128s-57.5-128-128-128c-32.75 0-63.75 12.5-87 34.25l34.25 34.5c4.75 4.5 6 11.5 3.5 17.25-2.5 6-8.25 10-14.75 10h-112c-8.75 0-16-7.25-16-16v-112c0-6.5 4-12.25 10-14.75 5.75-2.5 12.75-1.25 17.25 3.5l32.5 32.25c35.25-33.25 83-53 132.25-53 105.75 0 192 86.25 192 192z"></path></svg></span> <span class="pojo-a11y-toolbar-text">Reset</span> </a> </li> </ul> </div> </div> </nav>  <div id="cookie-notice" role="dialog" class="cookie-notice-hidden cookie-revoke-hidden 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