Clinical Trial

. 2015 Apr 21;313(15):1550-63.

doi: 10.1001/jama.2015.3253.

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

Salima Hacein-Bey Abina¹, H Bobby Gaspar², Johanna Blondeau³, Laure Caccavelli³, Sabine Charrier⁴, Karen Buckland², Capucine Picard⁵, Emmanuelle Six⁶, Nourredine Himoudi², Kimberly Gilmour², Anne-Marie McNicol², Havinder Hara², Jinhua Xu-Bayford⁷, Christine Rivat², Fabien Touzot⁸, Fulvio Mavilio⁹, Annick Lim¹⁰, Jean-Marc Treluyer¹¹, Sébastien Héritier¹², Francois Lefrère¹³, Jeremy Magalon³, Isabelle Pengue-Koyi⁸, Géraldine Honnet⁹, Stéphane Blanche¹², Eric A Sherman¹⁴, Frances Male¹⁴, Charles Berry¹⁴, Nirav Malani¹⁴, Frederic D Bushman¹⁴, Alain Fischer¹⁵, Adrian J Thrasher², Anne Galy⁴, Marina Cavazzana⁸

Affiliations

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.

PMID: 25898053
PMCID: PMC4942841
DOI: 10.1001/jama.2015.3253

Clinical Trial

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

Salima Hacein-Bey Abina et al. JAMA. 2015.

. 2015 Apr 21;313(15):1550-63.

doi: 10.1001/jama.2015.3253.

Authors

Affiliations

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.

PMID: 25898053
PMCID: PMC4942841
DOI: 10.1001/jama.2015.3253

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.

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Figures

**Figure 1. Longitudinal evaluation of gene marking in blood cells after gene therapy**
**(A)**. Gene marking in peripheral blood cells over time after gene therapy in patients P1 to P7, as expressed by vector copy numbers per cell (VCN) in PBMC and measured by q-PCR. (B). Gene marking in various blood cell subsets in each patient, expressed as VCN in: CD3+ T cells (filled squares); CD56+ NK cells (filled diamonds); CD19+ B cells (filled triangles); CD15+ neutrophils (open squares) and CD14+ monocytes (open circles).

**Figure 2. Lymphoid engraftment and expression of the WASp transgene measured by flow cytometry**
**(A)** Time course of lymphoid cell subsets recovery in blood after gene therapy: The total (open symbols) or WASp+ (filled symbols) levels of CD3+ T cells (squares), CD19+ B cells (triangles) and CD56+ NK cells (diamonds) were measured in blood over time. Tinted areas indicate values in aged-matched individuals. (B) WASp expression in lymphoid cell subpopulations at different times after gene therapy: Expression of WASp using specific antibodies is indicated by a thick line in CD3+ T lymphocytes, CD19+ B lymphocytes, CD56+ NK cells and CD4+ CD25+ FoxP3+ regulatory T cells (Tregs). Control antibody staining is shown by a gray overlay. WASp marking in T, B and NK cells of P1 to P7 performed respectively at months 30, 30, 6, 24, 24, 12 were shown. WASp marking in Tregs of P2, P4, P5 were performed respectively at months 30, 18, 18.

**Figure 3. Platelet reconstitution after gene therapy**
**(A)** The change over time in platelet counts in each individual patient. The lower normal value is indicated by a horizontal dotted bar. Filled triangles indicate platelet transfusions and open triangles indicate administration of romiplostim. **(B)** WASp expression in platelets, as measured by flow cytometry and represented as in Fig. 2B. (C) The correlation between platelet reconstitution and the number of transduced cells infused. The platelet count at last follow-up (Table 2) was plotted against the number of transduced CD34+ cells infused per kg of body weight, which was calculated by taking account of VCN values below 1.0 in the infused product (Table 1).

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Comment in

An emerging era of clinical benefit from gene therapy.
Malech HL, Ochs HD. Malech HL, et al. JAMA. 2015 Apr 21;313(15):1522-3. doi: 10.1001/jama.2015.2055. JAMA. 2015. PMID: 25898049 No abstract available.

References

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1. Zhu Q, Zhang M, Blaese RM, et al. The Wiskott-Aldrich syndrome and X-linked congenital thrombocytopenia are caused by mutations of the same gene. Blood. 1995 Nov 15;86(10):3797–3804. - PubMed
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Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome

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

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