A phase I/II, non-randomized, monocentric, open-label study of autologous CD34+ cells transduced with the G1XCGD lentiviral vector in patients with X-Linked Chronic Granulomatous Disease. - An ex vivo gene therapy study for X-CGD patients

开始日期2015-10-08

申办/合作机构

Genethon

NCT02333760 / Active, not recruiting临床1/2期IIT

Long Term Safety Follow up of Patients Enrolled in the Phase I/II Clinical Trial of Haematopoietic Stem Cell Gene Therapy for the Wiskott Aldrich Syndrome (GTG002-07 and GTG003-08).

An open follow up study of patients enrolled in the Phase 1/2 clinical trial of haematopoietic stem cell gene therapy for the Wiskott-Aldrich Syndrome and treated with autologous CD34+ cells transduced with the w1.6_hWASP_WPRE (VSVg) lentiviral vector.

开始日期2014-09-01

申办/合作机构

Genethon

100 项与 NADPH oxidase gene therapy(Généthon) 相关的临床结果

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100 项与 NADPH oxidase gene therapy(Généthon) 相关的转化医学

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100 项与 NADPH oxidase gene therapy(Généthon) 相关的专利（医药）

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项与 NADPH oxidase gene therapy(Généthon) 相关的文献（医药）

2018-06-01·Human Gene Therapy Clinical Development3区 · 医学

Non-Clinical Efficacy and Safety Studies on G1XCGD, a Lentiviral Vector for Ex Vivo Gene Therapy of X-Linked Chronic Granulomatous Disease

3区 · 医学

Article

作者: Brendel, Christian ; Galy, Anne ; Kunkel, Hana ; Charrier, Sabine ; Gaspar, Bobby ; Müller-Kuller, Uta ; Santilli, Giorgia ; Schambach, Axel ; Stein, Stefan ; Abriss, Daniela ; Grez, Manuel ; Rothe, Michael ; Modlich, Ute ; Thrasher, Adrian J.

Chronic granulomatous disease (CGD) is a debilitating primary immunodeficiency affecting phagocyte function due to the absence of nicotinamide dinucleotide phosphate (NADPH) oxidase activity. The vast majority of CGD patients in the Western world have mutations within the X-linked CYBB gene encoding for gp91^phox (NOX2), the redox center of the NADPH oxidase complex (XCGD). Current treatments of XCGD are not entirely satisfactory, and prior attempts at autologous gene therapy using gammaretrovirus vectors did not provide long-term curative effects. A new strategy was developed based on the use of the lentiviral vector G1XCGD expressing high levels of the gp91^phox transgene in myeloid cells. As a requisite for a clinical trial approval, standardized non-clinical studies were conducted in vitro and in mice in order to evaluate the pharmacodynamics and biosafety of the vector and the biodistribution of G1XCGD-transduced cells. Transduced CD34⁺ cells derived from XCGD patients engrafted and differentiated similarly to their non-transduced counterparts in xenograft mouse models and generated therapeutically relevant levels of NADPH activity in myeloid cells expressing gp91^phox. Expression of functional gp91^phox in hematopoietic cells did not affect their homing properties, which engrafted at high levels in mice. Extensive in vitro and in vivo genotoxicity studies found no evidence for adverse mutagenesis related to vector treatment. These studies paved the way for the approval of clinical trials in Europe and in the United States for the treatment of XCGD patients with G1XCGD gene-modified autologous hematopoietic cells.

2012-10-01·American Journal of Physiology-Endocrinology and Metabolism2区 · 医学

The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury

2区 · 医学

Article

作者: Koch, Walter ; Sun, Lu ; Ma, Yanzhuo ; Lau, Wayne B. ; Tao, Ling ; Wang, Haichang ; Gao, Erhe ; Yang, Lu ; Liu, Jingyi ; Qu, Yan ; Liu, Yi ; Lu, Xiaoyan ; Xu, Aibing ; Wang, Rutao ; Gao, Chao ; Lian, Kun ; Xia, Chenhai

The receptor for advanced glycation end products (RAGE) and thioredoxin (Trx) play opposing roles in diabetic myocardial ischemia-reperfusion (MI/R) injury. We recently demonstrated nitrative modification of Trx leads to its inactivation and loss of cardioprotection. The present study is to determine the relationship between augmented RAGE expression and diminished Trx activity pertaining to exacerbated MI/R injury in the diabetic heart. The diabetic state was induced in mice by multiple intraperitoneal low-dose streptozotocin injections. RAGE small-interfering RNA (siRNA) or soluble RAGE (sRAGE, a RAGE decoy) was via intramyocardial and intraperitoneal injection before MI/R, respectively. Mice were subjected to 30 min of myocardial infarction followed by 3 or 24 h of reperfusion. At 10 min before reperfusion, diabetic mice were randomized to receive EUK134 (peroxynitrite scavenger), recombinant hTrx-1, nitrated Trx-1, apocynin (a NADPH oxidase inhibitor), or 1400W [an inducible nitric oxide synthase (iNOS) inhibitor] administration. The diabetic heart manifested increased RAGE expression and Nε-(carboxymethyl)lysine (CML, major advanced glycation end product subtype) content, reduced Trx-1 activity, and increased Trx nitration after MI/R. RAGE siRNA or administration of sRAGE in diabetic mice decreased MI/R-induced iNOS and gp91phoxexpression, reduced Trx nitration, preserved Trx activity, and decreased infarct size. Apocynin or 1400W significantly decreased nitrotyrosine production and restored Trx activity. Conversely, administration of either EUK134 or reduced hTrx, but not nitrated hTrx, attenuated MI/R-induced superoxide production, RAGE expression, and CML content and decreased cardiomyocyte apoptosis in diabetic mice. Collectively, we demonstrate that RAGE modulates the MI/R injury in a Trx nitrative inactivation fashion. Conversely, nitrative modification of Trx blocked its inhibitory effect upon RAGE expression in the diabetic heart. This is the first direct evidence demonstrating the alternative cross talk between RAGE overexpression and nitrative Trx inactivation, suggesting that interventions interfering with their interaction may be novel means of mitigating diabetic MI/R injury.

100 项与 NADPH oxidase gene therapy(Généthon) 相关的药物交易

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