Gene Therapy for Purine Nucleoside Phosphorylase Deficiency (PNP)

描述(申请人提供)：这项建议将开发一项临床试验，通过将正常的PNP基因转移到受影响患者的造血干细胞中来治疗PNP缺乏症患者。在基因治疗领域进行了20年的研究后，有两项针对遗传性免疫缺陷的临床试验取得了有效的结果。第一个是法国的一项针对X连锁严重联合免疫缺陷(SCID)的逆转录病毒基因治疗试验，在该试验中，几种细胞因子受体的共同伽马链缺陷儿童的骨髓细胞暴露在编码缺失基因的逆转录病毒中，然后再注入患者体内。第二个试验是在意大利进行的，也是使用逆转录病毒转导骨髓细胞，但在这个病例中，引入了编码腺苷脱氨酶(ADA)的基因来治疗与ADA缺乏相关的SCID。至于X连锁SCID，几名患者对治疗的反应是恢复了细胞和体液免疫。我们建议治疗一种类似于ADA缺乏症的疾病；与嘌呤核苷磷酸化酶(PNP)缺失相关的免疫缺陷。这两种疾病都是嘌呤代谢异常导致脱氧核苷积累，这对淋巴细胞是有毒的。PNP缺陷患者细胞免疫功能低下，体液免疫功能异常。目前还没有治疗这种疾病的药物，因此缺乏匹配的异基因造血细胞移植捐赠者的患者没有临床选择。我们之前已经构建了编码人类PNP基因的逆转录病毒载体，并证明了从PNP缺陷患者获得的T细胞的代谢缺陷和恢复的免疫增殖功能的纠正。通过类比意大利ADA缺乏症试验的临床结果，我们预测PNP缺乏症也可以通过逆转录病毒转导PNP基因进入从PNP缺乏症患者获得的造血干细胞来治疗。这项临床试验的结果不仅对PNP缺乏症的治疗有意义，而且对其他免疫缺乏症的治疗也有意义。基因治疗为缺乏安全有效治疗的危及生命的疾病患者提供了一种新的治疗形式。嘌呤核苷磷酸化酶(PNP)缺乏症是一种过早致命性免疫缺陷，在大多数患者中治疗选择有限。这项拟议的临床试验的首要重要性将是为这些患者提供一种治疗选择；更重要的是，使用基因疗法安全有效地治疗人类疾病所获得的知识将对许多其他潜在威胁生命的疾病的治疗产生影响。

DESCRIPTION (provided by applicant): This proposal will develop a clinical trial to treat patients with purine nucleoside phosphorylase (PNP) deficiency with gene transfer of the normal PNP gene into hematopoietic stems cells of affected patients. After 20 years of research in the gene therapy field, there are two clinical trials for inherited immunodeficiency that have yielded an efficacious outcome. The first was a French trial of retroviral gene therapy for X-linked severe combined immunodeficiency (SCID), in which bone marrow cells from children deficient in the common gamma-chain for several cytokine receptors were exposed to a retrovirus encoding the missing gene and then reinfused into the patient. The second trial yielding an efficacious outcome was conducted in Italy, also using retroviral transduction of marrow cells, but in this case for introduction of the gene encoding adenosine deaminase (ADA) for treatment of SCID associated with deficiency of ADA. As for X-linked SCID, several patients have responded to the treatment with restored cellular and humoral immunity. We propose to treat a disease that is similar to ADA-deficiency; immunodeficiency associated with the absence of purine nucleoside phosphorylase (PNP). Both are diseases of aberrant purine metabolism resulting in accumulation of deoxynucleosides that are toxic for lymphocytes. PNP deficient patients suffer from deficient cellular immunity and aberrant humoral immunity. There is no medical therapy available for this disease, so patients who lack a matched donor for allogeneic hematopoietic cell transplant have no clinical options. We have previously generated retroviral vector encoding the human PNP gene and demonstrated correction of metabolic deficiency and restored immunoproliferative function in T-cells obtained from a PNP-deficient patient. By analogy to the clinical results generated in the Italian trial for ADA-deficiency, we predict that PNP-deficiency can also be treated by retroviral transduction of the PNP gene into hematopoietic stem cells obtained from PNP-deficient patients. Results from this clinical trial will have implications not only for the treatment of PNP deficiency but for the treatment of other immunodeficiencies as well. Gene therapy provides a new form of therapy for patients with life threatening diseases for which there are lacking safe and effective treatments. Purine nucleoside phosphorylase (PNP) deficiency is a prematurely lethal immunodeficiency with limited treatment options in the majority of patients. The primary importance of this proposed clinical trial will be providing a treatment option for these patients; and more importantly, the knowledge that gained in the use of gene therapy to safely and effectively treat human disease will have implications for the treatment of many other potentially life threatening diseases.