Gene therapy approaches for prevention of retinal degeneration in Usher syndrome

Williams, David S.; Chadha, Abhishek; Hazim, Roni A.; Gibbs, Daniel

doi:10.1038/gt.2016.81

Cited by 16 publications

(11 citation statements)

References 38 publications

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“… 62 , 63 , 64 Another controversial issue worth considering is the fact that post-mitotic cells are considered as lacking the HDR-mediated repair mechanism, 22 yet recent studies have detected HDR in retinal pigment epithelial cells and developed adult photoreceptors. 8 Nevertheless, even if HDR is considered as non-active, it has also been demonstrated that non-dividing cells do have a repair mechanism in the form of transcription-coupled homologous recombination, 65 enabling a repair pathway through an RNA template instead of ssODNs. The only major hindrance in using this technique would be the remote chance of introducing a mutation at potential off-target sites, thereby resulting in oncological consequences.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, more than one essential isoform of the USH2A gene is expressed in the retinal tissue, and augmentation therapy by delivery of one single cDNA would be insufficient. 8 Nevertheless, a suitable alternative now exists: genetic correction using gene editing strategies such as the CRISPR/Cas9 system, which holds enormous promise for in vivo and ex vivo genome editing-based therapies. 9 , 10 , 11 , 12 , 13 Furthermore, the close proximity of the two highly prevalent mutations in exon 13 of USH2A is convenient for using this particular technology.…”

Section: Introductionmentioning

confidence: 99%

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USH2A Gene Editing Using the CRISPR System

Fuster-García

García‐García

González-Romero

et al. 2017

Molecular Therapy - Nucleic Acids

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Usher syndrome (USH) is a rare autosomal recessive disease and the most common inherited form of combined visual and hearing impairment. Up to 13 genes are associated with this disorder, with USH2A being the most prevalent, due partially to the recurrence rate of the c.2299delG mutation. Excluding hearing aids or cochlear implants for hearing impairment, there are no medical solutions available to treat USH patients. The repair of specific mutations by gene editing is, therefore, an interesting strategy that can be explored using the CRISPR/Cas9 system. In this study, this method of gene editing is used to target the c.2299delG mutation on fibroblasts from an USH patient carrying the mutation in homozygosis. Successful in vitro mutation repair was demonstrated using locus-specific RNA-Cas9 ribonucleoproteins with subsequent homologous recombination repair induced by an engineered template supply. Effects on predicted off-target sites in the CRISPR-treated cells were discarded after a targeted deep-sequencing screen. The proven effectiveness and specificity of these correction tools, applied to the c.2299delG pathogenic variant of USH2A, indicates that the CRISPR system should be considered to further explore a potential treatment of USH.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

USH2A Gene Editing Using the CRISPR System

Fuster-García

García‐García

González-Romero

et al. 2017

Molecular Therapy - Nucleic Acids

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“…In the practice of gene therapy, the gene mutations responsible for the diseases are determined from analyzing the patients' genetic data. Based on the genetic information, appropriate techniques are used to replace the defective gene (Katz et al, 2017;Williams et al, 2017). Some people think that it is not in place to do gene therapy because replacing faulty gene is assumed as altering nature.…”

Section: Benefits Of Knowing Your Partner's Genome Informationmentioning

confidence: 99%

The impact of genome information on mate selection: From the African perspective

Adadey¹

2017

J. Med. Genet. Genomics

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Mate selection in humans is an important social activity which is central to every individual's life. The debate on the ethics of generating and using genetic information has been of concern to several researchers from the time of the completion of the human genome project till now. Some of the important questions to consider include whether it is ethical to generate and use genetic information in mate selection. This piece of literature is focused on critically evaluating the possible impacts of the knowledge of the genomic information on the choice of a life partner from the African perspective.

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“…Other strategies that should be investigated for increasing HDR efficiencies have been developed in recent years, such as the use of chemically modified or asymmetric ssODNs or the addition of NHEJ inhibitors to the culture medium (Maruyama et al 2015, Renaud et al 2016, Richardson et al 2016. Another controversial issue worth considering is the fact that post-mitotic cells are considered as lacking the HDR-mediated repair mechanism (Ran et al 2013b), yet recent studies have detected HDR in retinal pigment epithelial cells and developed adult photoreceptors (Williams et al 2017). Nevertheless, even if HDR is considered as non-active, it has also been demonstrated that non-dividing cells do have a repair mechanism in the form of transcription-coupled homologous recombination (Wei et al 2016), enabling a repair pathway through an RNA template instead of ssODNs.…”

Section: Analysis Of Edition Rates Using High-throughput Sequencingmentioning

confidence: 99%

“…The large size, up to 15 kb, of the USH2A coding sequence (GenBank: NM_206933) makes it difficult to develop a gene substitution therapy for patients with mutations in this gene. In addition, more than one essential isoform of the USH2A gene is expressed in the retinal tissue, and augmentation therapy by delivery of one single cDNA would be insufficient (Williams et al 2017). Nevertheless, a suitable alternative now exists: genetic correction using gene editing strategies such as the CRISPR/Cas9 system, which holds enormous promise for in vivo and ex vivo genome editing-based therapies (Cox et al 2015, Dai et al 2016, Long et al 2016, Nelson et al 2016, Tabebordbar et al 2016.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic approaches and development of genomic diagnostic tools for Usher syndrome

García¹

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Gracias también a todo mi grupillo de Philly que tan rápida y cálidamente me recibieron en su cuadrilla. En especial a Berta y Álvaro, por allanarme tanto el camino; y a Alba y Vicky, que desde el primer minuto os desvivisteis por que aprovechara al máximo mi estancia. Many thanks to Dr. Hakonarson and all the CAG members for allowing me the opportunity to learn from such a proficient and nice team during those six months. No me olvido tampoco del resto de amigos que, sólo con interesarse por mi trabajo o darme apoyo moral, también me ayudado durante estos años. Y, por supuesto, gracias a mi familia. A mis abuelos, porque sé que muchas de mis capacidades las he heredado de ellos, y porque sé la enorme ilusión que les habría hecho ser partícipes de este momento. En especial, a mi abuelo Jesús, quien sembró mi interés por la investigación y a quien le hubiese entusiasmado saber que finalmente desarrollé su profesión platónica. A Adrián, mil gracias (y me quedo corta). Es una gran suerte poder compartir las ilusiones e inquietudes del gremio con mi compañero de vida y de vocación. Gracias por sacarme de tantos apuros, porque literalmente sin ti me habría estancado. Gracias por escucharme cuando he necesitado desahogarme, por animarme y aconsejarme, y por disfrutar con mis éxitos. Gracias, en suma, por ser mi cómplice en todo. Gracias, de manera muy profunda, a mis padres, a quienes dedico esta tesis. Por innumerables motivos que, a fin de cuentas y de forma desvirtuada, se reducen a una esencia: por apoyarme siempre en todo, por las oportunidades que me habéis dado, por educarme como lo habéis hecho, y por vuestro desmedido cariño. Porque si he llegado hasta aquí, ha sido por vosotros, y porque si soy quien soy, es por vosotros. Gracias papá, gracias mamá, por ser como sois. Finalmente, mi más sincera gratitud a todos los pacientes y sus familiares que han participado en los estudios. Al fin y al cabo, todo esto es por vosotros. Gracias por vuestra confianza. Quiero creer que nuestro empeño, si no el de otros, acabará traduciéndose en una solución.

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Gene therapy approaches for prevention of retinal degeneration in Usher syndrome

Cited by 16 publications

References 38 publications

USH2A Gene Editing Using the CRISPR System

USH2A Gene Editing Using the CRISPR System

The impact of genome information on mate selection: From the African perspective

Therapeutic approaches and development of genomic diagnostic tools for Usher syndrome

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