IN VIVO ADA GENE DELIVERY FOR THE TREATMENT OF SCID

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 严重联合免疫缺陷（SCID）是最极端的原发性免疫缺陷，由于压倒性感染，大多数儿童的寿命为1-2年，无需治疗。腺苷脱氨酶（ADA）缺陷型SCID占人类SCID病例的约20%，在不同遗传类型的SCID中是独特的，因为它是由于缺乏酶（ADA）。 虽然ADA在所有组织中表达，但ADA酶的缺乏对淋巴细胞的存活最为关键，并且在ADA缺乏的情况下，毒性代谢物在淋巴细胞中积累并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，使用牛聚乙二醇结合腺苷脱氨酶（PEG-ADA）的酶替代疗法（ERT）可有益于ADA缺陷型SCID患者。 然而，PEG-ADA ERT仅提供免疫功能的部分恢复，并且其需要持续的非常昂贵的酶制剂的每两周肌肉内注射。这些研究的目的是在人类婴儿中进行试验之前，作为临床前研究，评估幼猴中的载体药代动力学、剂量测定和生物分布。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基因表达。这些研究对于开始考虑将这种方法转化为人类ADA缺陷型SCID儿科患者至关重要。

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.