Phase I/II trial of lentiviral vector mediated gene therapy for Adenosine Deaminase deficiency

腺苷脱氨酶缺乏症（ADA）会导致血液中白细胞的严重发育问题，并导致一种称为严重联合免疫缺陷症（SCID，有时也被称为“泡泡婴儿”）的疾病。受感染的儿童无法抵抗感染，如果不进行治疗，将在出生后的第一年死亡。治疗的选择非常有限。如果能找到一个好的供体，骨髓移植是有效的，但如果必须使用一个不相关或不匹配的供体，这个过程可能是危险的，10个孩子中有3-5个死于移植的影响。另一种治疗方法是定期注射ADA酶，但这并不能完全纠正白细胞问题，儿童仍然容易受到感染。基因治疗是一种将ADA基因的工作副本引入患者细胞的方法，这样他们就可以生长出新的免疫系统。这比移植有一些优势，因为它使用的是孩子自己的细胞。我们和其他人以前用这种方法治疗过ADA患者，10个孩子中有7个能够生长出新的免疫系统。然而，为了将基因携带到患者细胞中，我们和其他人使用了一种被称为γ逆转录病毒载体（GRV）的失活病毒。不幸的是，在其他疾病的基因治疗中，grv导致白血病（一种血癌）的发展，试验不得不停止。基于这些原因，我们希望开发一种更安全的方法将基因导入患者细胞。我们计划使用一种不同的载体，称为慢病毒载体（LV）。我们已经在实验室测试了lv，结果表明它们比GRVs安全得多，而且它们在纠正免疫系统方面也同样出色。我们现在想看看它们是否能有效安全地治疗病人。在本研究中，我们计划通过基因治疗治疗10例没有良好供体移植的ADA SCID患者。我们将使用已准备用于患者的LV载体将ADA基因的工作副本引入骨髓细胞。我们将对患者进行3年的随访，看看他们是否能生长出新的免疫系统，也看看这种治疗是否安全。如果我们在这10名患者中看到良好的治疗反应，那么我们希望这将成为ADA缺乏症患者的标准治疗方法。

Adenosine deaminase deficiency(ADA) causes a severe problem with the development of the white cells in the blood and leads to a disease called severe combined immunodeficiency (SCID - also sometimes termed 'bubble babies'). Affected children are unable to fight infection and without treatment will die in the first year of life. The options for treatment are very limited. A bone marrow transplant is effective if a good donor can be found but in cases where an unrelated or mismatched donor has to be used, the procedure can be dangerous and 3-5 out of 10 children die from the effects of the transplant. Another treatment is regular injections of the ADA enzyme but this does not fully correct the white cells problems and children still remain vulnerable to infection.Gene therapy is way of introducing a working copy of the ADA gene into patients cells so that they can grow a new immune system. This has some advantages over a transplant because it uses the child's own cells. We and others have treated ADA patients in this way previously and 7 out of 10 children have been able to grow a new immune system. However, to carry the gene into the patient cells we and others used a disabled virus called a gammaretroviral vector (GRV). Unfortunately, in gene therapy treatments for other diseases, GRVs caused the development of leukaemia (a blood cancer) and trials had to be stopped. For these reasons, we want to develop a safer way of introducing the gene into patient cells. We are planning to use a different vector called a lentiviral vector (LV). We have tested LVs in the laboratory and shown that they are much safer than GRVs but also that they are equally good at correcting the immune system.We now want to see if they can treat patients effectively and safely. In this study, we plan to treat 10 patients with ADA SCID who do not have a good donor for transplant by gene therapy. We will introduce a working copy of the ADA gene into their bone marrow cells using a LV vector that has been prepared for use in patients. We will follow patients for 3 years to see if they can grow a new immune system and also to see if this treatment is safe. If we see a good response to the treatment in these 10 patients, then we hope that this will become a standard treatment for patients with ADA deficiency.