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Auteur Sherman EA
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Hacein-Bey Abina S, Gaspar HB, Blondeau J, et al.
JAMA. Journal of the American Medical Association, 2015, 313, 15, p. 1550-63
Revue : JAMA. Journal of the American Medical Association, 313, 15 Titre : Outcomes following gene therapy in patients with severe Wiskott-Aldrich syndrome. Type de document : Article Auteurs : Hacein-Bey Abina S ; Gaspar HB ; Blondeau J ; Caccavelli L ; Charrier S ; Buckland K ; Picard C ; Six E ; Himoudi N ; Gilmour K ; McNicol AM ; Hara H ; Xu-Bayford J ; Rivat C ; Touzot F ; Mavilio F ; Lim A ; Treluyer JM ; Héritier S ; Lefrère F ; Magalon J ; Pengue-Koyi I ; Honnet G ; Blanche S ; Sherman EA ; Male F ; Berry C ; Malani N ; Bushman FD ; Fischer A ; Thrasher AJ ; Galy A ; Cavazzana M Année de publication : 21/04/2015 Pages : p. 1550-63 Langues : Anglais (eng) Résumé : 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.
Pubmed / DOI : DOI : 10.1001/jama.2015.3253 / Pubmed : 25898053 En ligne : http://www.ncbi.nlm.nih.gov/pubmed/25898053
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