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Genome Med. 2018 Sep 28;10(1):70. doi: 10.1186/s13073-018-0580-z.

T cell dynamics and response of the microbiota after gene therapy to treat X-linked severe combined immunodeficiency.

Author information

1
Department of Microbiology, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, PA, 19104-6076, USA.
2
Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
3
Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Paris, France.
4
Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
5
Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA.
6
Boston Children's Hospital, Karp 08125.3, 300 Longwood Avenue, Boston, MA, 02115, USA.
7
Laboratory of Host Defenses, Laboratory of Clinical Infectious Diseases, Immune Deficiency Genetics Section, NIAID, NIH, Bethesda, MD, USA.
8
Department of Medicine, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, PA, 19104-6076, USA.
9
Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, Hôpital Kremlin-Bicêtre, Assistance Publique-Hôpitaux de Paris, 78, r. du Général-Leclerc, 94270, Le-Kremlin-Bicêtre, France.
10
UTCBS CNRS UMR 8258, INSERM U1022, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, Chimie Paris-Tech, 4 av. de l'observatoire, 75006, Paris, France.
11
Departments of Microbiology, Immunology & Molecular Genetics; and Pediatrics, University of California, Los Angeles, USA.
12
Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
13
Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France.
14
Pediatric Hemato-Immunology Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
15
Collège de France, Paris, France.
16
Havard Stem Cell Institute, Harvard Medical School, Boston, MA, 02115, USA.
17
Department of Microbiology, University of Pennsylvania School of Medicine, 3610 Hamilton Walk, Philadelphia, PA, 19104-6076, USA. bushman@pennmedicine.upenn.edu.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

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