CRISPR/Cas9‐mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse

The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system...

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Bibliographic Details
Published inEMBO molecular medicine Vol. 8; no. 5; pp. 477 - 488
Main Authors Guan, Yuting, Ma, Yanlin, Li, Qi, Sun, Zhenliang, Ma, Lie, Wu, Lijuan, Wang, Liren, Zeng, Li, Shao, Yanjiao, Chen, Yuting, Ma, Ning, Lu, Wenqing, Hu, Kewen, Han, Honghui, Yu, Yanhong, Huang, Yuanhua, Liu, Mingyao, Li, Dali
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.05.2016
EMBO Press
John Wiley and Sons Inc
Springer Nature
Subjects
Adenoviridae - genetics
Animal models
Animals
Child
Coagulation factors
CRISPR
CRISPR-Cas Systems
Deoxyribonucleic acid
Disease
Disease Models, Animal
DNA
EMBO16
EMBO18
Expression vectors
Factor IX - genetics
Factor IX deficiency
Gene Editing - methods
Gene loci
Gene therapy
Genetic disorders
Genetic Therapy - methods
Genetic Vectors
Genome editing
Genomes
Hemophilia
hemophilia B
Hemophilia B - pathology
Hemophilia B - therapy
Hemostasis
Hepatocytes
Hereditary diseases
Humans
Male
Males
Mice
monogenetic disease
Mutation
Mutation, Missense
Phenotypes
Point mutation
Recombination, Genetic
Research Article
Toxicity
Treatment Outcome
Twins
Mali
China
genome editing
gene therapy
monogenetic disease
hemostasis
hemophilia B
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Abstract The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas‐mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies. Synopsis CRISPR/Cas9‐mediated genome editing holds promise for the treatment of genetic disorders, but its potential for hemophilia treatment is unknown. This study shows that in genome correction via Cas9 is a feasible therapeutic strategy for hemophilia B. Identification a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. Generation of three distinct genetically modified mouse models and confirmation that the mouse harboring the novel Y371D mutation is a new hemophilia B model. Hepatic in situ correction of the point mutation in the F9 allele via CRISPR/Cas9‐mediated genome editing was sufficient to restore hemostasis in hemophilia B mice. Graphical Abstract CRISPR/Cas9‐mediated genome editing holds promise for the treatment of genetic disorders, but its potential for hemophilia treatment is unknown. This study shows that in genome correction via Cas9 is a feasible therapeutic strategy for hemophilia B.
AbstractList The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas‐mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies. Synopsis CRISPR/Cas9‐mediated genome editing holds promise for the treatment of genetic disorders, but its potential for hemophilia treatment is unknown. This study shows that in genome correction via Cas9 is a feasible therapeutic strategy for hemophilia B. Identification a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. Generation of three distinct genetically modified mouse models and confirmation that the mouse harboring the novel Y371D mutation is a new hemophilia B model. Hepatic in situ correction of the point mutation in the F9 allele via CRISPR/Cas9‐mediated genome editing was sufficient to restore hemostasis in hemophilia B mice. CRISPR/Cas9‐mediated genome editing holds promise for the treatment of genetic disorders, but its potential for hemophilia treatment is unknown. This study shows that in genome correction via Cas9 is a feasible therapeutic strategy for hemophilia B.
The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas‐mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies. Synopsis CRISPR/Cas9‐mediated genome editing holds promise for the treatment of genetic disorders, but its potential for hemophilia treatment is unknown. This study shows that in genome correction via Cas9 is a feasible therapeutic strategy for hemophilia B. Identification a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. Generation of three distinct genetically modified mouse models and confirmation that the mouse harboring the novel Y371D mutation is a new hemophilia B model. Hepatic in situ correction of the point mutation in the F9 allele via CRISPR/Cas9‐mediated genome editing was sufficient to restore hemostasis in hemophilia B mice. Graphical Abstract CRISPR/Cas9‐mediated genome editing holds promise for the treatment of genetic disorders, but its potential for hemophilia treatment is unknown. This study shows that in genome correction via Cas9 is a feasible therapeutic strategy for hemophilia B.
The X-linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas-mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies.
Abstract The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas‐mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies.
The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX , hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR /Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR /Cas‐mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies.
The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas‐mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies.
The X-linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas-mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies.The X-linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice. After treatment, hemophilia B mice receiving naked DNA constructs exhibited correction of over 0.56% of F9 alleles in hepatocytes, which was sufficient to restore hemostasis. In contrast, the adenoviral delivery system resulted in a higher corrective efficiency but no therapeutic effects due to severe hepatic toxicity. Our studies suggest that CRISPR/Cas-mediated in situ genome editing could be a feasible therapeutic strategy for human hereditary diseases, although an efficient and clinically relevant delivery system is required for further clinical studies.
Author Ma, Lie
Zeng, Li
Huang, Yuanhua
Shao, Yanjiao
Hu, Kewen
Li, Qi
Chen, Yuting
Wu, Lijuan
Ma, Ning
Liu, Mingyao
Li, Dali
Lu, Wenqing
Han, Honghui
Sun, Zhenliang
Ma, Yanlin
Wang, Liren
Yu, Yanhong
Guan, Yuting
AuthorAffiliation 6 Department of Molecular and Cellular Medicine The Institute of Biosciences and Technology Texas A&M University Health Science Center Houston TX USA
4 Fengxian Hospital affiliated to Southern Medical University Shanghai China
1 Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai China
3 Department of Obstetrics and Gynecology Nanfang Hospital Southern Medical University Guangzhou China
5 Bioray Laboratories Inc. Shanghai China
2 Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research Hainan Reproductive Medical Center the Affiliated Hospital of Hainan Medical University Hainan Medical University Haikou China
AuthorAffiliation_xml – name: 2 Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research Hainan Reproductive Medical Center the Affiliated Hospital of Hainan Medical University Hainan Medical University Haikou China
– name: 4 Fengxian Hospital affiliated to Southern Medical University Shanghai China
– name: 6 Department of Molecular and Cellular Medicine The Institute of Biosciences and Technology Texas A&M University Health Science Center Houston TX USA
– name: 5 Bioray Laboratories Inc. Shanghai China
– name: 1 Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai China
– name: 3 Department of Obstetrics and Gynecology Nanfang Hospital Southern Medical University Guangzhou China
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  surname: Guan
  fullname: Guan, Yuting
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
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  givenname: Yanlin
  surname: Ma
  fullname: Ma, Yanlin
  email: mayl1990@foxmail.com
  organization: Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Hainan Reproductive Medical Center, the Affiliated Hospital of Hainan Medical University, Hainan Medical University, Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University
– sequence: 3
  givenname: Qi
  surname: Li
  fullname: Li, Qi
  organization: Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Hainan Reproductive Medical Center, the Affiliated Hospital of Hainan Medical University, Hainan Medical University
– sequence: 4
  givenname: Zhenliang
  surname: Sun
  fullname: Sun, Zhenliang
  organization: Fengxian Hospital affiliated to Southern Medical University
– sequence: 5
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  surname: Ma
  fullname: Ma, Lie
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
– sequence: 6
  givenname: Lijuan
  surname: Wu
  fullname: Wu, Lijuan
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
– sequence: 7
  givenname: Liren
  surname: Wang
  fullname: Wang, Liren
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
– sequence: 8
  givenname: Li
  surname: Zeng
  fullname: Zeng, Li
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
– sequence: 9
  givenname: Yanjiao
  surname: Shao
  fullname: Shao, Yanjiao
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
– sequence: 10
  givenname: Yuting
  surname: Chen
  fullname: Chen, Yuting
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
– sequence: 11
  givenname: Ning
  surname: Ma
  fullname: Ma, Ning
  organization: Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Hainan Reproductive Medical Center, the Affiliated Hospital of Hainan Medical University, Hainan Medical University
– sequence: 12
  givenname: Wenqing
  surname: Lu
  fullname: Lu, Wenqing
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
– sequence: 13
  givenname: Kewen
  surname: Hu
  fullname: Hu, Kewen
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
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  givenname: Honghui
  surname: Han
  fullname: Han, Honghui
  organization: Bioray Laboratories Inc
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  givenname: Yanhong
  surname: Yu
  fullname: Yu, Yanhong
  organization: Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University
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  givenname: Yuanhua
  surname: Huang
  fullname: Huang, Yuanhua
  organization: Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Hainan Reproductive Medical Center, the Affiliated Hospital of Hainan Medical University, Hainan Medical University
– sequence: 17
  givenname: Mingyao
  surname: Liu
  fullname: Liu, Mingyao
  email: myliu@bio.ecnu.edu.cn
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Department of Molecular and Cellular Medicine, The Institute of Biosciences and Technology, Texas A&M University Health Science Center
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  givenname: Dali
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  email: dlli@bio.ecnu.edu.cn
  organization: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
BackLink https://www.ncbi.nlm.nih.gov/pubmed/26964564$$D View this record in MEDLINE/PubMed
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Issue 5
Keywords genome editing
gene therapy
monogenetic disease
hemostasis
hemophilia B
Language English
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http://creativecommons.org/licenses/by/4.0
2016 The Authors. Published under the terms of the CC BY 4.0 license.
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Snippet The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome...
The X-linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome...
The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX , hemophilia B, is a disease ideally suited for gene therapy with genome...
Abstract The X‐linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with...
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SubjectTerms Adenoviridae - genetics
Animal models
Animals
Child
Coagulation factors
CRISPR
CRISPR-Cas Systems
Deoxyribonucleic acid
Disease
Disease Models, Animal
DNA
EMBO16
EMBO18
Expression vectors
Factor IX - genetics
Factor IX deficiency
Gene Editing - methods
Gene loci
Gene therapy
Genetic disorders
Genetic Therapy - methods
Genetic Vectors
Genome editing
Genomes
Hemophilia
hemophilia B
Hemophilia B - pathology
Hemophilia B - therapy
Hemostasis
Hepatocytes
Hereditary diseases
Humans
Male
Males
Mice
monogenetic disease
Mutation
Mutation, Missense
Phenotypes
Point mutation
Recombination, Genetic
Research Article
Toxicity
Treatment Outcome
Twins
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Title CRISPR/Cas9‐mediated somatic correction of a novel coagulator factor IX gene mutation ameliorates hemophilia in mouse
URI https://link.springer.com/article/10.15252/emmm.201506039
https://onlinelibrary.wiley.com/doi/abs/10.15252%2Femmm.201506039
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Volume 8
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