Core--Human Applications

人类应用核心的主要目的是确保涉及 在基因治疗核心中心内进行的对患有囊性纤维化（CF）和其他遗传疾病的患者的基因治疗试验的设计和实施是适当的，以最大限度地提高这些基因治疗试验的安全性、有效性和效率。核心的目标是：1）与核心中心的研究者合作设计和实施临床前研究，以确保在启动人体试验之前收集必要的安全性和有效性数据，2）为人体试验的设计和开发提供咨询，3）为患者招募、研究实施提供人员，基因治疗试验的数据收集和统计分析，4）提供监管咨询，5）确保通过该P-30计划进行的基因治疗试验中招募的所有研究参与者的安全，6）向新的研究人员提供有关进行涉及人类基因治疗的临床试验的教育和咨询。在上一个赠款周期（1999-2003），人类应用核心（HAC）协助设计，进行和完成了三项人体试验，两个涉及腺相关病毒（AAV）的气溶胶递送一个涉及将逆转录病毒介导的人CD 18 cDNA体外转导至白细胞粘附患者的外周血再生细胞左前降支（LAD）缺乏。在更新期的第一年，HAC将协助开发五项拟议的人体试验： 1. AAV介导的标记基因人胎盘碱性磷酸酶的递送， 囊性纤维化患者的呼吸道上皮（Dusty米勒，PI） 2.将雾化tgAAVCF递送至囊性纤维化患者的下气道（协作 （Target Genetics Corporation）。 3.临床前研究，以评估基因替代疗法在患有 原发性免疫缺陷，Wiskott-Aldrich综合征（WAS），利用逆转录病毒或 慢病毒介导的载体系统（大卫罗林斯，PI）。 4.临床前研究，旨在评估评估 使用含有截短的但功能性的微小肌营养不良蛋白基因的AAV载体用于 来自肌营养不良症患者的肌细胞的体内转导。 5.一项关于长期输注葡萄糖调节胰岛素的安全性的I期研究， 通过逆转录病毒转导的自体或 同种异体血管平滑肌细胞置于皮下生物隔离装置（Theracyte）中。 核心的好处是整合资源，确保人体试验的设计 并回答基因治疗领域的科学问题。

The primary aim of the Human Applications Core is to ensure that human trials involving patients with Cystic Fibrosis (CF) and other genetic disorders conducted within the Core Center for Gene Therapy are properly designed and implemented to maximize safety, validity and efficiency of these gene therapy trials. The objectives of the Core are to 1) collaborate with investigators within the Core Center in the design and implementation of preclinical studies to assure that necessary safety and efficacy data have been collected prior to initiation of human trials, 2) provide consultation for design and development of human trials, 3) provide personnel for patient enrollment, study implementation, data collection and statistical analyses of gene therapy trials, 4) provide regulatory consultation, 5) ensure safety of all research participants enrolled in gene therapy trials conducted through this P-30 program, 6) provide education and consultation to new investigators regarding conduct of clinical trials involving human gene therapy. In the previous grant cycle (1999-2003), the Human Applications Core (HAC) assisted in the design, conduct and completion of three human trials, two involving aerosol delivery of adeno-associated viruses (AAV) to the lower airway of patients with Cystic Fibrosis and one involving ex vivo transduction of retroviral mediated human CD18 cDNA to peripheral blood repopulating cells of patients with Leukocyte Adherence Deficiency (LAD). In the first year of the renewal period, the HAC will assist in development of five proposed human trials: 1. AAV mediated delivery of a marker gene, human placental alkaline phosphatase, to respiratory epithelium of patients with Cystic Fibrosis (Dusty Miller, PI) 2. Aerosolized tgAAVCF delivery to lower airway of patients with Cystic Fibrosis (collaboration with Targeted Genetics Corporation). 3. Preclinical study to assess the feasibility of gene replacement therapy in individuals with the primary immunodeficiency, Wiskott-Aldrich Syndrome (WAS) utilizing either a retroviral or lentiviral mediated vector system (David Rawlings, PI). 4. Preclinical study to assess the feasibility and optimal patient population to evaluate the safety of utilizing AAV vectors containing truncated yet functional mini dystrophin genes for in vivo transduction of myocytes from patients with muscular dystrophy. 5. A Phase 1 study of the safety of long-term delivery of glucose-regulated insulin to individuals with Type 1 Diabetes Mellitus (IDDM) by retroviral transduced autologous or allogeneic vascular smooth cells housed in subcutaneous bioisolator devices (Theracyte(R)). The benefits of the Core are to consolidate resources and ensure that human trials are designed and conducted to answer proper scientific questions in the field of gene therapy.