Title |
T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency
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Published in |
Genome Medicine, September 2018
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DOI | 10.1186/s13073-018-0580-z |
Pubmed ID | |
Authors |
Erik L. Clarke, A. Jesse Connell, Emmanuelle Six, Nadia A. Kadry, Arwa A. Abbas, Young Hwang, John K. Everett, Casey E. Hofstaedter, Rebecca Marsh, Myriam Armant, Judith Kelsen, Luigi D. Notarangelo, Ronald G. Collman, Salima Hacein-Bey-Abina, Donald B. Kohn, Marina Cavazzana, Alain Fischer, David A. Williams, Sung-Yun Pai, Frederic D. Bushman |
Abstract |
Mutation of the IL2RG gene results in a form of severe combined immune deficiency (SCID-X1), which has been treated successfully with hematopoietic stem cell gene therapy. SCID-X1 gene therapy results in reconstitution of the previously lacking T cell compartment, allowing analysis of the roles of T cell immunity in humans by comparing before and after gene correction. Here we interrogate T cell reconstitution using four forms of high throughput analysis. (1) Estimation of the numbers of transduced progenitor cells by monitoring unique positions of integration of the therapeutic gene transfer vector. (2) Estimation of T cell population structure by sequencing of the recombined T cell receptor (TCR) beta locus. (3) Metagenomic analysis of microbial populations in oropharyngeal, nasopharyngeal, and gut samples. (4) Metagenomic analysis of viral populations in gut samples. Comparison of progenitor and mature T cell populations allowed estimation of a minimum number of cell divisions needed to generate the observed populations. Analysis of microbial populations showed the effects of immune reconstitution, including normalization of gut microbiota and clearance of viral infections. Metagenomic analysis revealed enrichment of genes for antibiotic resistance in gene-corrected subjects relative to healthy controls, likely a result of higher healthcare exposure. This multi-omic approach enables the characterization of multiple effects of SCID-X1 gene therapy, including T cell repertoire reconstitution, estimation of numbers of cell divisions between progenitors and daughter T cells, normalization of the microbiome, clearance of microbial pathogens, and modulations in antibiotic resistance gene levels. Together, these results quantify several aspects of the long-term efficacy of gene therapy for SCID-X1. This study includes data from ClinicalTrials.gov numbers NCT01410019, NCT01175239, and NCT01129544. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 4 | 25% |
France | 1 | 6% |
Canada | 1 | 6% |
India | 1 | 6% |
Unknown | 9 | 56% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 9 | 56% |
Scientists | 4 | 25% |
Science communicators (journalists, bloggers, editors) | 2 | 13% |
Practitioners (doctors, other healthcare professionals) | 1 | 6% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 64 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 15 | 23% |
Student > Ph. D. Student | 8 | 13% |
Student > Bachelor | 7 | 11% |
Student > Master | 6 | 9% |
Student > Doctoral Student | 3 | 5% |
Other | 8 | 13% |
Unknown | 17 | 27% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 12 | 19% |
Medicine and Dentistry | 7 | 11% |
Agricultural and Biological Sciences | 7 | 11% |
Immunology and Microbiology | 4 | 6% |
Nursing and Health Professions | 2 | 3% |
Other | 8 | 13% |
Unknown | 24 | 38% |