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Lancet Haematol ; 6(5): e239-e253, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30981783


BACKGROUND: Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. METHODS: We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with (number NCT01515462) and EudraCT (number 2009-017346-32). FINDINGS: Between April 20, 2010, and Feb 26, 2015, nine patients (all male) were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1-12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5-5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8-35·6) before gene therapy to 66·7% (55·7-98·6) at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1-31·0) to 76·6% (53·1-98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44-3·72) per patient-year of observation (PYO) in the year before gene therapy to 0·31 (0·04-1·11) per PYO in the second year after gene therapy and 0·17 (0·00-0·93) per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 109 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20-50 × 109 per L in one patient, 50-100 × 109 per L in five patients, and more than 100 × 109 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%) of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy. INTERPRETATION: Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available. FUNDING: Italian Telethon Foundation, GlaxoSmithKline, and Orchard Therapeutics.

Terapia Genética , Vetores Genéticos/genética , Células-Tronco Hematopoéticas/metabolismo , Lentivirus/genética , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/terapia , Criança , Pré-Escolar , Feminino , Terapia Genética/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Itália , Masculino , Mutação , Linfócitos T/imunologia , Linfócitos T/metabolismo , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Síndrome de Wiskott-Aldrich/sangue , Síndrome de Wiskott-Aldrich/diagnóstico , Proteína da Síndrome de Wiskott-Aldrich/genética
Front Vet Sci ; 5: 272, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30425997


The ability to DNA fingerprint Mycobacterium bovis isolates helped to define the role of wildlife in the persistence of bovine tuberculosis in New Zealand. DNA fingerprinting results currently help to guide wildlife control measures and also aid in tracing the source of infections that result from movement of livestock. During the last 5 years we have developed the ability to distinguish New Zealand (NZ) M. bovis isolates by comparing the sequences of whole genome sequenced (WGS) M. bovis samples. WGS provides much higher resolution than our other established typing methods and greatly improves the definition of the regional localization of NZ M. bovis types. Three outbreak investigations are described and results demonstrate how WGS analysis has led to the confirmation of epidemiological sourcing of infection, to better definition of new sources of infection by ruling out other possible sources, and has revealed probable wildlife infection in an area considered to be free of infected wildlife. The routine use of WGS analyses for sourcing new M. bovis infections will be an important component of the strategy employed to eradicate bovine TB from NZ livestock and wildlife.

Lancet Neurol ; 11(2): 131-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22226929


BACKGROUND: Monoclonal antibody therapy against α4ß-integrin is efficacious in patients with multiple sclerosis (MS) with some safety concerns. We assessed the safety and efficacy of firategrast, a small oral anti-α4ß-integrin molecule, in patients with relapsing remitting MS. METHODS: We did a multicentre, phase 2, randomised, double-blind, placebo-controlled, dose-ranging study in participants with clinically definite relapsing-remitting MS. A 24-week treatment period was followed by 12 weeks of core follow-up and 40 weeks of extended follow-up. Participants were randomly assigned, via computer-generated block randomisation in a 1:2:2:2 ratio, to receive one of four treatments twice a day: firategrast 150 mg, firategrast 600 mg, or firategrast 900 mg (women) or 1200 mg (men), or placebo. Brain scans were obtained at 4-week intervals to the end of core follow-up. The primary outcome was cumulative number of new gadolinium-enhancing brain lesions during the treatment phase and was analysed using a generalised linear model with an underlying negative binomial distribution, adjusted for sex, baseline number of new gadolinium-enhancing lesions, and country. This study is registered with, NCT00395317. FINDINGS: Of 343 individuals enrolled, 49 received firategrast 150 mg, 95 received firategrast 600 mg, 100 received firategrast 900 mg or 1200 mg, and 99 received placebo. A 49% reduction (95% CI 21·2-67·6; p=0·0026) in the cumulative number of new gadolinium-enhancing lesions was seen for the 900 mg or 1200 mg firategrast group (n=92, mean number of lesions 2·69 [SE 1·18]) versus the placebo group (90, 5·31 [1·18]). In the 600 mg group (86, 4·12 [SE 1·19]), a non-significant 22% reduction (95% CI -21·3 to 49·7; p=0·2657) occurred in mean number of new gadolinium-enhanced lesions relative to placebo; for the 150 mg group (47, 9·51 [SE 1·24]), a 79% increase (95% CI 4·1-308·1; p=0·0353) occurred relative to placebo. Firategrast was generally well tolerated at all doses. The frequency of all adverse events was similar across all treatment groups except for an increased rate of urinary tract infections in the high-dose firategrast group. No cases of progressive multifocal leukoencephalopathy or evidence of reactivation of JC virus were identified. INTERPRETATION: This study showed efficacy on imaging endpoints for firategrast at the highest dose tested, and suggests that further investigation of oral short-acting α4ß integrin blockade therapies is warranted. FUNDING: GlaxoSmithKline.

Anticorpos Monoclonais/administração & dosagem , Integrina alfa4beta1/antagonistas & inibidores , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Gadolínio , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/patologia , Placebos , Resultado do Tratamento