Retroviral Vector-mediated Liver Gene Therapy for MPS I

描述(由申请人提供)： 粘多糖病I(MPS I)是由于α-L艾杜糖苷酶(IDUA)活性低下引起的溶酶体贮积性疾病。它会导致骨骼和关节异常、心脏病、生长迟缓和角膜混浊，通常与早期死亡和智力低下有关。我们先前已经证明，新生儿注射表达β-葡萄糖醛酸酶(GUSB)的逆转录病毒载体可以有效地转导肝细胞，肝细胞分泌甘露糖6-磷酸化的GUSB，可被其他器官摄取。这导致了相关疾病MPS VII在小鼠和狗身上的许多临床表现的改善。将这种方法扩展到治疗MPS I有两个原因，这是本项目的目标。首先，MPS I犬通常对IDUA产生强大的免疫反应，这将使人们更好地了解这种基因治疗方法的免疫学后果。在零突变的人类中使用这种方法之前，确定这一点将是很重要的。其次，MPS I是MPS综合征中最常见的，活产儿发生率为1：100,000，而MPS II相当罕见。如果这种方法被证明是安全和有效的，MPS I的较高发生率将有助于确定要治疗的患者。该项目将包括开发一种表达犬IDUA基因的逆转录病毒载体。最初的研究将把载体运送到患有MPS I的新生小鼠或狗的肝细胞中，将对动物进行器官和血液中的酶水平、对clDUA的免疫反应以及溶酶体储存病的临床和病理表现的评估。虽然新生儿的治疗有很多优点，可能会降低免疫反应，但大多数MPS I患者在出生后就被诊断出来了。因此，我们将测试这种逆转录病毒载体是否可以传递给患有MPS I的幼年动物，以及这是否更有可能产生免疫反应。如果出现免疫反应，将在基因治疗时给予免疫调节剂以防止其发展。最后，严重MPS的毁灭性特征之一是智力低下，这种肝脏导向的方法可能在治疗这方面的疾病方面无效。因此，我们将测试修改肝脏产生的IDUA蛋白是否可以改善血液向大脑的输送。该项目可能导致将该方法应用于患有 MPS I在未来，尽管这里不建议进行临床试验。

DESCRIPTION (provided by applicant): Mucopolysaccharidosis I (MPS I) is a lysosomal storage disease due to deficient alpha-L-iduronidase (IDUA)activity. It results in bone and joint abnormalities, cardiac disease, growth retardation, and corneal clouding, and is usually associated with early death and mental retardation. We have previously demonstrated that neonatal injection of a retroviral vector expressing beta-glucuronidase (GUSB) results in efficient transduction of hepatocytes, which secrete mannose 6-phosphorylated GUSB that can be taken up by other organs. This results in improvement in many of the clinical manifestations of the related disorder, MPS VII, in both mice and dogs. There are two reasons for extending this approach to treat MPS I, which is the goal of this project. First, MPS I dogs usually make potent immune responses to IDUA, which will allow the immunological consequences of this gene therapy approach to be better understood. This will be important "to define prior to using this approach in humans with null mutations". Second, MPS I is the most common of the MPS syndromes with an incidence of 1:100,000 live births, while MPS VII is quite rare. The higher incidence of MPS I will facilitate identifying patients to treat should this approach prove to be safe and effective. This project will involve development of a retroviral vector expressing the canine IDUA cDNA. Initial studies will deliver the vector to hepatocytes of newborn mice or dogs with MPS I. Animals will be evaluated for enzyme levels in organs and blood, immunological responses to clDUA, and clinical and pathological manifestations of lysosomal storage disease. Although treatment of newborns has many advantages and may reduce immunological responses, most patients with MPS I are diagnosed well after birth. We will therefore test if this retroviral vector can be delivered to juvenile animals with MPS I, and if this is more likely to generate an immune response. If immune responses develop, immune modulators will be given at the time of gene therapy to prevent their development. Finally, one of the devastating features of severe MPS is mental retardation, and this liver-directed approach may be ineffective at treating this aspect of disease. We will therefore test if modification of the IDUA protein produced by the liver can improve delivery to the brain from the blood. This project may result in application of this approach for patients with MPS I in the future, although clinical trials are not proposed here.