Format

Send to

Choose Destination
JAMA. 2015 Apr 21;313(15):1550-63. doi: 10.1001/jama.2015.3253.

Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome.

Author information

1
Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France3Unité de.
2
Section of Molecular and Cellular Immunology, University College London Institute of Child Health, London, England6Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
3
Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France.
4
INSERM U951, Unité Mixte de Recherche S951, Molecular Immunology and Innovative Biotherapies, University of Evry, Evry, France8Genethon, Evry, France.
5
Centre d'Étude des Déficits Immunitaires, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France10Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Departmen.
6
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France12INSERM Unité Mixte de Recherche 1163, Laboratory of Human Lymphohematopoiesis, Paris, France.
7
Department of Clinical Immunology, Hospital National Health Service Foundation Trust, London, England.
8
Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France2Biotherapy Clinical Investigation Center, Groupe Hospitalier Universitaire Ouest, Assistance Publique-Hôpitaux de Paris, INSERM, Paris, France10Paris D.
9
Genethon, Evry, France.
10
Groupe Immunoscope, Immunology Department, Institut Pasteur, Paris, France.
11
Clinical Research Center Necker-Enfants Malades and Cochin Hospital Assistance Publique-Hôpitaux de Paris, Paris Descartes University.
12
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris, Paris, France.
13
Biotherapy Department, Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
14
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia.
15
Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France11Immunology and Pediatric Hematology Department, Assistance Publique-Hôpitaux de Paris, Paris, France12INSERM Unité Mixte de Recherche 1163, Laboratory of Human Lymphohematop.

Abstract

IMPORTANCE:

Wiskott-Aldrich syndrome is a rare primary immunodeficiency associated with severe microthrombocytopenia. Partially HLA antigen-matched allogeneic hematopoietic stem cell (HSC) transplantation is often curative but is associated with significant comorbidity.

OBJECTIVE:

To assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome.

DESIGN, SETTING, AND PARTICIPANTS:

Gene-corrected autologous HSCs were infused in 7 consecutive patients with severe Wiskott-Aldrich syndrome lacking HLA antigen-matched related or unrelated HSC donors (age range, 0.8-15.5 years; mean, 7 years) following myeloablative conditioning. Patients were enrolled in France and England and treated between December 2010 and January 2014. Follow-up of patients in this intermediate analysis ranged from 9 to 42 months.

INTERVENTION:

A single infusion of gene-modified CD34+ cells with an advanced lentiviral vector.

MAIN OUTCOMES AND MEASURES:

Primary outcomes were improvement at 24 months in eczema, frequency and severity of infections, bleeding tendency, and autoimmunity and reduction in disease-related days of hospitalization. Secondary outcomes were improvement in immunological and hematological characteristics and evidence of safety through vector integration analysis.

RESULTS:

Six of the 7 patients were alive at the time of last follow-up (mean and median follow-up, 28 months and 27 months, respectively) and showed sustained clinical benefit. One patient died 7 months after treatment of preexisting drug-resistant herpes virus infection. Eczema and susceptibility to infections resolved in all 6 patients. Autoimmunity improved in 5 of 5 patients. No severe bleeding episodes were recorded after treatment, and at last follow-up, all 6 surviving patients were free of blood product support and thrombopoietic agonists. Hospitalization days were reduced from a median of 25 days during the 2 years before treatment to a median of 0 days during the 2 years after treatment. All 6 surviving patients exhibited high-level, stable engraftment of functionally corrected lymphoid cells. The degree of myeloid cell engraftment and of platelet reconstitution correlated with the dose of gene-corrected cells administered. No evidence of vector-related toxicity was observed clinically or by molecular analysis.

CONCLUSIONS AND RELEVANCE:

This study demonstrated the feasibility of the use of gene therapy in patients with Wiskott-Aldrich syndrome. Controlled trials with larger numbers of patients are necessary to assess long-term outcomes and safety.

PMID:
25898053
PMCID:
PMC4942841
DOI:
10.1001/jama.2015.3253
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center