Gene Therapy for Purine Nucleoside Phosphorylase Deficiency (PNP)

嘌呤核苷磷酸化酶缺乏症 (PNP) 的基因治疗

• 批准号: 7239735
• 负责人: KEVIN S BAKER
• 金额: $ 11.21万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7239735
• 关键词: Affect; Allogenic; Bone Marrow Cells; Cell Transplants; Cell physiology; Cells; Cellular Immunity; Child; Clinical; Clinical Research; Clinical Treatment; Clinical Trials; Cytokine Receptors; Disease; Documentation; Gene Transfer; Genes; Hematopoietic; Hematopoietic stem cells; Human; Humoral Immunities; Immune System Diseases; Immunologic Deficiency Syndromes; Inherited; Interleukin 2 Receptor Gamma; Italy; Knowledge; Life; Lymphocyte; Manuals; Marrow; Medical; Metabolic; Methods; Outcome; Patients; Phase; Phosphorylase a; Procedures; Processed Genes; Protocols documentation; Purine-Nucleoside Phosphorylase; Purine-Nucleoside Phosphorylase Deficiency; Research; Retroviral Vector; Retroviridae; Severe Combined Immunodeficiency; Standards of Weights and Measures; T-Lymphocyte; X-Linked Severe Combined Immunodeficiency; adenosine deaminase; adenosine deaminase deficiency; gene therapy; gene therapy clinical trial; human disease; human subject; purine metabolism; retroviral transduction

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.

描述（由申请人提供）：本提案将开展一项临床试验，通过将正常PNP基因转移到受影响患者的造血干细胞中来治疗嘌呤核苷磷酸化酶（PNP）缺乏症患者。经过20年的基因治疗领域的研究，有两个遗传性免疫缺陷的临床试验已经产生了有效的结果。第一个是法国对X连锁严重联合免疫缺陷（SCID）进行的逆转录病毒基因疗法试验，其中来自缺乏几种细胞因子受体的共同γ链的儿童的骨髓细胞暴露于编码缺失基因的逆转录病毒，然后重新注入患者体内。在意大利进行的第二项试验产生了有效的结果，也使用了骨髓细胞的逆转录病毒转导，但在这种情况下，引入了编码腺苷脱氨酶（ADA）的基因，用于治疗与ADA缺乏相关的SCID。至于X连锁的SCID，一些患者对治疗有反应，恢复了细胞和体液免疫。我们建议治疗一种类似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。两者都是嘌呤代谢异常导致对淋巴细胞有毒的脱氧核苷积聚的疾病。PNP缺陷型患者患有细胞免疫缺陷和异常体液免疫。目前尚无治疗该病的药物，因此缺乏匹配供体进行异基因造血细胞移植的患者没有临床选择。我们先前已经产生了编码人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细胞中的代谢缺陷的纠正和免疫增殖功能的恢复。通过类比意大利ADA缺乏症试验中产生的临床结果，我们预测PNP缺乏症也可以通过将PNP基因逆转录病毒转导到从PNP缺乏症患者获得的造血干细胞中来治疗。这项临床试验的结果不仅对PNP缺乏症的治疗有意义，而且对其他免疫缺陷症的治疗也有意义。基因治疗为缺乏安全有效治疗方法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死的免疫缺陷，在大多数患者中治疗选择有限。这项拟议的临床试验的主要重要性将是为这些患者提供一种治疗选择;更重要的是，在使用基因治疗安全有效地治疗人类疾病方面获得的知识将对许多其他潜在的危及生命的疾病的治疗产生影响。