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Am J Hum Genet. 2016 Jan 7;98(1):90-101. doi: 10.1016/j.ajhg.2015.11.012. Epub 2015 Dec 10.

Spell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders.

Author information

1
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
2
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
3
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
4
Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
5
INSERM UMRS974, Centre National de la Recherche Scientifique FRE3617, Center for Research in Myology, Université Pierre et Marie Curie (Paris 6), Sorbonne Universités, 47 Boulevard de l'Hôpital, 75013 Paris, France.
6
Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital, London WC1N 1EH, UK.
7
NIHR Biomedical Research Centre, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
8
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
9
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
10
Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
11
Program in Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada. Electronic address: ronald.cohn@sickkids.ca.

Abstract

Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals. We show that an adapted version of CRISPR/Cas9 increases the amount of utrophin, a known disease modifier in Duchenne muscular dystrophy (DMD). Furthermore, we demonstrate preferential elimination of the dominant-negative FGFR3 c.1138G>A allele in fibroblasts of an individual affected by achondroplasia. Using a previously undescribed approach involving single guide RNA, we successfully removed large genome rearrangement in primary cells of an individual with an X chromosome duplication including MECP2. Moreover, removal of a duplication of DMD exons 18-30 in myotubes of an individual affected by DMD produced full-length dystrophin. Our findings establish the far-reaching therapeutic utility of CRISPR/Cas9, which can be tailored to target numerous inherited disorders.

PMID:
26686765
PMCID:
PMC4716669
DOI:
10.1016/j.ajhg.2015.11.012
[Indexed for MEDLINE]
Free PMC Article
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