A CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system

Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient an...

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Veröffentlicht in:Nature communications Jg. 10; H. 1; S. 1668 - 10
Hauptverfasser: LaFleur, Martin W., Nguyen, Thao H., Coxe, Matthew A., Yates, Kathleen B., Trombley, Justin D., Weiss, Sarah A., Brown, Flavian D., Gillis, Jacob E., Coxe, Daniel J., Doench, John G., Haining, W. Nicholas, Sharpe, Arlene H.
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Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 10.04.2019
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ISSN:2041-1723, 2041-1723
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Abstract Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8 + T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo. The use of functional genomics in primary immune cells has been limited by inefficient vector delivery and risk of perturbing cell states. Here the authors present CHimeric IMmune Editing (CHIME) for in vivo evaluation of gene function and pooled screening approaches.
AbstractList Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8 + T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo. The use of functional genomics in primary immune cells has been limited by inefficient vector delivery and risk of perturbing cell states. Here the authors present CHimeric IMmune Editing (CHIME) for in vivo evaluation of gene function and pooled screening approaches.
The use of functional genomics in primary immune cells has been limited by inefficient vector delivery and risk of perturbing cell states. Here the authors present CHimeric IMmune Editing (CHIME) for in vivo evaluation of gene function and pooled screening approaches.
Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8+ T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo.Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8+ T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo.
Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8 + T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo.
Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8+ T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo. The use of functional genomics in primary immune cells has been limited by inefficient vector delivery and risk of perturbing cell states. Here the authors present CHimeric IMmune Editing (CHIME) for in vivo evaluation of gene function and pooled screening approaches.
Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8 T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo.
ArticleNumber 1668
Author Coxe, Matthew A.
Weiss, Sarah A.
Doench, John G.
Nguyen, Thao H.
Yates, Kathleen B.
LaFleur, Martin W.
Gillis, Jacob E.
Coxe, Daniel J.
Haining, W. Nicholas
Sharpe, Arlene H.
Trombley, Justin D.
Brown, Flavian D.
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  organization: Department of Microbiology and Immunobiology, Harvard Medical School, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital
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  givenname: Thao H.
  surname: Nguyen
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  organization: Department of Microbiology and Immunobiology, Harvard Medical School, Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital
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  givenname: Justin D.
  orcidid: 0000-0002-3856-3138
  surname: Trombley
  fullname: Trombley, Justin D.
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  givenname: Sarah A.
  orcidid: 0000-0002-4155-0346
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  fullname: Weiss, Sarah A.
  organization: Department of Pediatric Oncology, Dana-Farber Cancer Institute
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  givenname: Flavian D.
  surname: Brown
  fullname: Brown, Flavian D.
  organization: Department of Microbiology and Immunobiology, Harvard Medical School, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital
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  givenname: Jacob E.
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  organization: School of Energy, Matter, and Transport Engineering at Arizona State University
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  organization: Broad Institute of Harvard and Massachusetts Institute of Technology
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  surname: Haining
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  surname: Sharpe
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  email: Arlene_Sharpe@hms.harvard.edu
  organization: Department of Microbiology and Immunobiology, Harvard Medical School, Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital, Broad Institute of Harvard and Massachusetts Institute of Technology
BackLink https://www.ncbi.nlm.nih.gov/pubmed/30971695$$D View this record in MEDLINE/PubMed
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Snippet Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics...
The use of functional genomics in primary immune cells has been limited by inefficient vector delivery and risk of perturbing cell states. Here the authors...
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Adaptive Immunity - genetics
Adaptive systems
Animals
Autoimmune diseases
Autoimmunity
Bone marrow
Bone Marrow Transplantation
Cancer
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
Cell Line, Tumor
Cell Lineage - genetics
Cell Lineage - immunology
Chlorocebus aethiops
Clonal deletion
CRISPR
CRISPR-Cas Systems - genetics
Disease Models, Animal
Feasibility Studies
Female
Gene Transfer Techniques
Genes
Genetic screening
Genetic Testing - methods
Genetic Vectors - genetics
Genomics
Genomics - methods
HEK293 Cells
Humanities and Social Sciences
Humans
Immune system
Immunity, Innate - genetics
Lymphocytes
Lymphocytes T
Lymphocytic Choriomeningitis - genetics
Lymphocytic Choriomeningitis - immunology
Lymphocytic Choriomeningitis - virology
Lymphocytic choriomeningitis virus - immunology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
multidisciplinary
Protein Tyrosine Phosphatase, Non-Receptor Type 2 - genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 2 - immunology
PTPN2 protein
RNA, Guide, CRISPR-Cas Systems - genetics
Science
Science (multidisciplinary)
Screening
Therapeutic applications
Transplantation Chimera
Vero Cells
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Title A CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system
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