In Vivo ADA Gene Delivery for the Treatment of SCID

用于治疗 SCID 的体内 ADA 基因传递

基本信息

批准号：
7249606
负责人：
Donald B Kohn
金额：
$ 47.89万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7249606
关键词：
Accounting Acute Adenosine Age Allogeneic Bone Marrow Transplantation Animal Model Animals Biochemical Biodistribution Blood Cells Blood Circulation Bos taurus Cattle Cell Death Child Chronic Clinical Complementary DNA Deficiency Diseases Deoxyadenosines Development Disease Drug Kinetics Ectopic Expression Enzymes Functional disorder Gene Delivery Gene Expression Gene Transfer Genes Genetic Goals Hepatic Hepatocyte Human Immune Immunity Immunologics Infant Infection Injection of therapeutic agent Intravenous Knock-out Knockout Mice Lentivirus Vector Life Liver Longevity Luciferases Lymphocyte Macaca mulatta Measures Metabolic Metabolic Diseases Methods Mus Newborn Animals Patients Plasma Polyethylene Glycols Preparation Principal Investigator Proteins Public Health Relative (related person)Reporter Genes Role SCID Mice Source Therapeutic Therapeutic Effect Tissues Toxic effect Toxicology Translations Treatment Protocols adenosine deaminase adenosine deaminase deficiency deoxyadenosine disease phenotype dosimetry enzyme activity enzyme replacement therapy extracellular immune function improved in vivo intravenous administration mouse model neonate novel novel therapeutics preclinical study programs promoter restoration tripolyphosphate vector vector genome

项目摘要

DESCRIPTION (provided by applicant): Deficiency of adenosine deaminase (ADA) is responsible for 20% of human severe combined immune deficiency (SCID). Current therapies for ADA-deficient SCID have clinical benefits, but each approach has limitations. Thus, development of novel therapeutic approaches are important for this form of SCID and these advances may have therapeutic applications for other primary immune deficiencies, blood cell diseases and metabolic disorders. The unique pathophysiology of ADA-deficient SCID, with the potential for trans-correction of the immune deficiency by ectopic expression of ADA, may allow a novel therapy to be developed. We have determined in a murine ADA gene knock-out mouse model that a single I.V. administration of a lentiviral vector carrying a normal human ADA cDNA leads to systemic ADA gene delivery and ADA enzyme expression that restores immunity and significantly prolongs survival. The central hypothesis of this proposal is that: In vivo systemic delivery of a normal ADA gene will be clinically beneficial for correcting the biochemical and immunologic abnormalities of ADA-deficient SCID, providing efficacy similar to or greater than that of exogenous enzyme replacement therapy, but as a single treatment, rather than as a chronic regimen. To assess this hypothesis, we will 1. optimize in vivo gene delivery by IV vector administration in ADA gene knock-out mice, 2. evaluate the mechanisms of the effect from in vivo ADA gene delivery, and 3. define large animal vector dosimetry, pharmacokinetics, bio-distribution and toxicology as pre-clinical studies. The overall goals of this Proposal are to optimize the efficacy of systemic ADA gene delivery, to gain better understanding of the mechanisms of the therapeutic effects and to perform initial pre- clinical studies in a large animal model. Relevance to public health: Primary immune deficiency diseases are serious, life-threatening disorders with patients often developing severe, life-threatening infections in the first years of life. Current therapies for these diseases have significant efficacy, but remain sub-optimal. Therefore, it is imperative to continue to develop new and improved methods to treat primary immune deficiency diseases and that is the primary goal of this project have significant efficacy, but remain sub-optimal.

描述（由申请人提供）：腺苷脱氨酶（ADA）的缺乏负责人类严重合并免疫缺陷（SCID）的20％。当前对ADA缺陷SCID的疗法具有临床益处，但每种方法都有局限性。因此，新型治疗方法的开发对于这种SCID形式很重要，这些进步可能对其他原发性免疫缺陷，血细胞疾病和代谢性疾病具有治疗应用。 ADA缺陷型SCID的独特病理生理，具有通过ADA异位表达对免疫缺陷进行反校正的潜力，可以开发出一种新型的疗法。我们已经在鼠ADA基因敲除小鼠模型中确定了单个i.v.携带正常人ADA cDNA的慢病毒载体的给药会导致全身性ADA基因递送和ADA酶表达，可恢复免疫力并显着延长生存率。该提议的核心假设是：正常ADA基因的体内全身输送将在临床上有益于纠正ADA缺陷SCID的生化和免疫学异常，从而提供了类似于或更大的功效，而不是外来酶再载剂疗法的功效，但作为单一的治疗方法，而不是单一的治疗方法。为了评估这一假设，我们将1。通过在ADA基因敲除小鼠中iV载体给药优化体内基因递送，2。评估体内ADA基因递送的效果机制，3。定义大型动物载体剂量法，药物，药物，生物分布和毒素学（如预先研究）。该提案的总体目标是优化系统性ADA基因递送的功效，以更好地了解治疗作用的机制，并在大型动物模型中进行初步的临床研究。与公共卫生有关：原发性免疫缺陷疾病是严重的，威胁生命的疾病，患者在生命的第一年经常会出现严重的，威胁生命的感染。这些疾病的当前疗法具有明显的疗效，但仍然是最佳的。因此，必须继续开发新的和改进的方法来治疗原发性免疫缺陷疾病，这是该项目的主要目标具有明显的功效，但仍然是最佳的。