IN VIVO ADA GENE DELIVERY FOR THE TREATMENT OF SCID

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 严重的联合免疫缺陷(SCID)是最极端的原发免疫缺陷，大多数儿童由于压倒性感染而未接受治疗，寿命为1-2年。腺苷脱氨酶(ADA)缺陷的SCID约占人类SCID病例的20%，在不同的SCID基因类型中是独一无二的，因为它是缺乏酶(ADA)的结果。虽然ADA在所有组织中都有表达，但ADA酶的缺失对淋巴细胞的生存至关重要，在缺乏ADA的情况下，有毒代谢物会在淋巴细胞中积聚，导致严重的代谢紊乱和细胞死亡。除了骨髓移植可用于治疗SCID外，应用聚乙二醇腺苷脱氨酶(PEGADA)的酶替代疗法(ERT)对ADA缺陷的SCID患者也是有益的。然而，PEG-ADA ERT只能部分恢复免疫功能，而且需要持续两周一次的肌肉注射这种非常昂贵的酶制剂。这些研究的目的是评估媒介在婴儿猴体内的药代动力学、剂量学和生物分布，作为在人类婴儿试验之前的临床前研究。我们将测量载体血浆清除率、载体生物分布和载体基因组持久性，并测量体内ADA基因的表达。这些研究对于开始考虑将这一方法翻译到人类ADA缺乏的SCID儿童患者是至关重要的。

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.