IN VIVO ADA GENE DELIVERY FOR THE TREATMENT OF SCID

用于治疗 SCID 的体内 ADA 基因递送

基本信息

批准号：
7959084
负责人：
Donald B Kohn
金额：
$ 10.67万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2010-04-30
项目状态：
已结题

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Severe combined immune deficiency (SCID) represents the most extreme primary immune deficiency with a life-span of 1-2 years in most children without therapy due to overwhelming infections. Adenosine deaminase (ADA)-deficient SCID, which accounts for ~20% of human cases of SCID, is unique among the different genetic types of SCID in that it results from the absence of an enzyme (ADA). Although ADA is expressed in all tissues, the absence of ADA enzyme is most critical to the survival of lymphocytes and, in the absence of ADA, toxic metabolites accumulate in lymphocytes and causes severe metabolic derangements and cell death. Besides bone marrow transplantation that can be used to treat SCID, enzyme replacement therapy (ERT) with bovine polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) can be beneficial to patients with ADA-deficient SCID. However, PEG-ADA ERT only provides partial restoration of immune function and it requires ongoing bi-weekly intramuscular injections of the very expensive enzyme preparation. The objective of these studies is to assess vector pharmacokinetics, dosimetry, and biodistribution in infant monkeys as pre-clinical studies prior to testing in human infants. We will measure vector plasma clearance, vector biodistribution, and vector genome persistence, and measure in vivo ADA gene expression. These studies are essential to initiate considerations of translation of this approach to human ADA-deficient SCID pediatric patients.

该副本是利用众多研究子项目之一由NIH/NCRR资助的中心赠款提供的资源。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构是对于中心，这不一定是调查员的机构。严重的联合免疫缺陷（SCID）代表了最极端的原发性免疫缺陷，大多数儿童的寿命为1-2岁。腺苷脱氨酶（ADA）缺乏SCID，占人类SCID病例的约20％，在不同的遗传类型的SCID中是独一无二的，因为它是由于缺乏酶（ADA）而引起的。尽管ADA在所有组织中均表达，但ADA酶的缺乏对于淋巴细胞的存活最为至关重要，并且在没有ADA的情况下，有毒代谢产物积累在淋巴细胞中，并导致严重的代谢危险和细胞死亡。除了可用于治疗SCID的骨髓移植外，还用牛聚乙烯乙二醇偶联的腺苷脱氨酶（PEG-ADA）对酶替代疗法（ERT）可能对患有ADA缺乏SCID的患者有益。但是，PEG-ADA ERT仅提供部分恢复免疫功能，并且需要每两周一次的肌内注射非常昂贵的酶制备。这些研究的目的是评估婴儿猴子作为临床前研究的载体药代动力学，剂量法和生物分布。我们将测量载体等离子体清除率，载体生物分布和载体基因组持久性，并在体内ADA基因表达中测量。这些研究对于开始考虑这种方法对人ADA缺乏的SCID小儿患者的翻译至关重要。