Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome.

Blood
Nicholas HubbardTroy R Torgerson

Abstract

Loss of CD40 ligand (CD40L) expression or function results in X-linked hyper-immunoglobulin (Ig)M syndrome (X-HIGM), characterized by recurrent infections due to impaired immunoglobulin class-switching and somatic hypermutation. Previous attempts using retroviral gene transfer to correct murine CD40L expression restored immune function; however, treated mice developed lymphoproliferative disease, likely due to viral-promoter-dependent constitutive CD40L expression. These observations highlight the importance of preserving endogenous gene regulation in order to safely correct this disorder. Here, we report efficient, on-target, homology-directed repair (HDR) editing of the CD40LG locus in primary human T cells using a combination of a transcription activator-like effector nuclease-induced double-strand break and a donor template delivered by recombinant adeno-associated virus. HDR-mediated insertion of a coding sequence (green fluorescent protein or CD40L) upstream of the translation start site within exon 1 allowed transgene expression to be regulated by endogenous CD40LG promoter/enhancer elements. Additionally, inclusion of the CD40LG 3'-untranslated region in the transgene preserved posttranscriptional regulation. Expression...Continue Reading

References

Oct 1, 1991·Current Opinion in Biotechnology·A Aruffo
Oct 1, 1994·The Journal of Experimental Medicine·C CauxJ Banchereau
Jun 1, 1995·European Journal of Immunology·D GrafR A Kroczek
Mar 31, 1995·The Journal of Biological Chemistry·G J MazzeiJ Y Bonnefoy
Jun 16, 1997·The Journal of Experimental Medicine·E CarboneS Zappacosta
Jun 1, 1997·Current Opinion in Immunology·C van Kooten, J Banchereau
Oct 29, 1997·Molecular and Cellular Biology·D G Taghian, J A Nickoloff
Jan 27, 2000·Journal of Leukocyte Biology·C van Kooten, J Banchereau
Jul 4, 2001·Nature Reviews. Molecular Cell Biology·K Kinoshita, T Honjo
Mar 14, 2003·Current Opinion in Immunology·Amy L Kenter
Aug 21, 2004·Pediatric Research·Amos Etzioni, Hans D Ochs
Jan 22, 2005·Immunological Reviews·Alain FischerMarina Cavazzana-Calvo
Nov 8, 2008·European Journal of Health Law·M J H Kenter
May 12, 2009·Immunological Reviews·Raul ElguetaRandolph J Noelle
Feb 26, 2010·British Journal of Haematology·E Graham Davies, Adrian J Thrasher
Jul 12, 2011·Nature Methods·Michael T CertoAndrew M Scharenberg
Oct 26, 2013·Nucleic Acids Research·Richard A VoitMatthew H Porteus
Apr 3, 2014·Nature Reviews. Genetics·Hyongbum Kim, Jin-Soo Kim
Dec 17, 2014·Nature Biotechnology·Richard L FrockFrederick W Alt
Feb 14, 2015·Nature Reviews. Immunology·Shane Crotty
Feb 14, 2015·Nature Reviews. Immunology·Tomohiro KurosakiWataru Ise
Jul 29, 2015·Proceedings of the National Academy of Sciences of the United States of America·Kathrin SchumannAlexander Marson

❮ Previous
Next ❯

Citations

Oct 11, 2016·The Journal of Allergy and Clinical Immunology·Isabelle MeytsJean-Laurent Casanova
Nov 8, 2016·Nature·Daniel P DeverMatthew H Porteus
Oct 5, 2016·The Journal of Allergy and Clinical Immunology·M Teresa de la MorenaChaim M Roifman
Jan 11, 2017·Hämostaseologie·Simone A HaasToni Cathomen
Apr 8, 2017·Nature Medicine·Tatjana I CornuToni Cathomen
Sep 25, 2017·American Journal of Medical Genetics. Part a·Hans D Ochs, Daniel Petroni
May 28, 2016·Blood·Matthew H Porteus
Aug 16, 2017·Human Gene Therapy·Claudio MussolinoToni Cathomen
Jan 27, 2019·Expert Review of Clinical Immunology·Tabata T FrançaAntonio Condino-Neto
Jan 26, 2018·Nature Protocols·Rasmus O BakMatthew H Porteus
Jul 13, 2019·Human Molecular Genetics·Claire BoothAdrian J Thrasher
Sep 17, 2020·Human Gene Therapy·Rajeev RaiAlessia Cavazza
Feb 11, 2020·Frontiers in Pediatrics·Benedicte Neven, Francesca Ferrua
Jun 5, 2020·Science Advances·M GoodwinR Bacchetta
Apr 25, 2018·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·T M GeelM G Rots
Mar 12, 2019·The New England Journal of Medicine·Matthew H Porteus
Apr 1, 2020·F1000Research·Giorgia Bucciol, Isabelle Meyts
Jun 10, 2017·Current Stem Cell Reports·Juliette M K M Delhove, Waseem Qasim
Mar 7, 2017·Allergy, Asthma, and Clinical Immunology : Official Journal of the Canadian Society of Allergy and Clinical Immunology·Xiaobai XuEyal Grunebaum
Nov 19, 2019·Frontiers in Pediatrics·Frank J T StaalMarina Cavazzana
Nov 15, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Warren AndersonDavid J Rawlings
May 18, 2020·Current Hematologic Malignancy Reports·Theodore L Roth
Oct 21, 2020·Expert Opinion on Biological Therapy·Kritika Chetty, Claire Booth
Dec 19, 2020·British Journal of Haematology·Thomas A Fox, Claire Booth
Oct 10, 2018·Current Opinion in Allergy and Clinical Immunology·Caroline Y Kuo
May 31, 2019·Emerging Topics in Life Sciences·Roland Preece, Christos Georgiadis
Dec 7, 2020·British Journal of Haematology·Neelam PanchalClaire Booth
Jan 7, 2021·HemaSphere·Benjamin C Houghton, Claire Booth
May 31, 2019·Emerging Topics in Life Sciences·Suk See De Ravin, Julie Brault
Feb 5, 2021·Journal of Clinical Medicine·Christi T Salisbury-Ruf, Andre Larochelle
Feb 20, 2021·Nature Reviews. Genetics·Gavin I EllisJames L Riley
Apr 6, 2021·Synthetic Biology·Mingqi XieMartin Fussenegger
Jul 3, 2021·Cells·Lola KonialiMarina Kleanthous
Jul 1, 2021·Clinical & Translational Immunology·Lukman O AfolabiXiaochun Wan
Mar 18, 2020·Genes & Diseases·Zhi-Yong ZhangFang Zhang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cell-Type Specific Viral Vectors

Viral vectors are used in biological research and therapy to deliver genetic material into cells. However, the efficiency of viral vectors varies depending on the cell type. Here is the latest research on cell-type-specific viral vectors.

Cell-Type-Specific Viral Vectors (ASM)

Viral vectors are used in biological research and therapy to deliver genetic material into cells. However, the efficiency of viral vectors varies depending on the cell type. Here is the latest research on cell-type-specific viral vectors.

AAV-based Gene Therapy

Adeno-associated virus (AAV)-based gene therapy is a biological vector that is being researched to be used as a potential therapeutic option. This gene therapy is designed to insert fragments of DNA into targeted cells to help treat diseases, such as hemophilia a. Discover the latest research on AAV-based gene therapy here.

CAR-T cells

Chimeric antigen receptor (CAR) T cells are cells that are genetically engineered to recognize and target specific proteins. The ability of these cells to recognize cancer antigens and eliminate tumor cells have transformed cancer immunotherapy approaches. Here is the latest research on CAR-T cells.

Cell-Type-Specific Viral Vectors

Viral vectors are used in biological research and therapy to deliver genetic material into cells. However, the efficiency of viral vectors varies depending on the cell type. Here is the latest research on cell-type-specific viral vectors.