Gene Therapy for Urea Cycle Disorders

描述(由申请人提供)：这是宾夕法尼亚大学和儿童国家医学中心提出的一项申请，目的是为现有的P01项目续期资金，该项目的标题是“尿素循环障碍的基因疗法”。我们实现了本P01本4年周期的主要目标。构建了一个临床候选载体：AAVs，表达肝脏特异的TBG启动子的鸟氨酸转氨甲基酶(OTC)密码子优化的cDNAs。在与我们的伦理咨询委员会密切磋商后，决定在对起病较晚但严重OTC缺乏症(OTCD)的婴儿进行I期临床试验时对临床候选进行初步评估。我们将使用与P01竞争续签分开的机制为临床试验提供资金。在我们的临床前研究中，我们确定了几个在考虑临床试验之前应该解决的问题，这些患者患有严重的OTCD，在新生儿时期出现危及生命的高氨血症。在新生的小鼠和猴子中进行高水平的基因转移是可行的，然而，由于在发育中的新生肝脏的环境中稀释，它减少到低水平。我们也担心一些新生儿发病患者的T细胞反应，因为他们可能有零等位基因，无法删除对OTC正常版本起反应的T细胞。最后，由于母体抗体的被动转移，一些新生儿将对AAVs具有预先存在的免疫力。项目I将解决与T细胞对转基因编码的OTC的反应有关的问题，并将尝试设计载体基因组，以便在目标细胞群体增殖时进行复制。项目II将评估新的药物干预措施，这些干预措施可能会增强疗效较差的基因疗法的疗效。项目III将设计AAVs衣壳，以逃避某种程度的预先存在的中和抗体。这些项目将得到专门研究向量、细胞形态和动物模型的核心实验室的支持。在续订申请结束时交付的是第二代临床候选药物，在辅助药物治疗的背景下，适合在新生儿起病的OTCD患者中进行评估。

DESCRIPTION (provided by applicant): This is an application from the University of Pennsylvania and the Children's National MedicalCenter to renew funding of an existing P01 entitled "Gene Therapy of Urea Cycle Disorders." We achieved the primary objectives of the current 4 year cycle of this P01. A Clinical Candidate vector was established: AAVS expressing a codon-optimized cDNA for ornithine transcarbamylase (OTC) from the liver-specific TBG promoter. In close consultation with our Ethics Advisory Board, it was decided to initially evaluate the Clinical Candidate in a phase I clinical trial in infants with late onset but severe OTC deficiency (OTCD). We will be using mechanisms to fund the clinical trial separate from this P01 competing renewal. In the conduct of our preclinical studies, we identified several issues that should be addressed before considering clinical trials in those with severe OTCD who present with life-threatening episodes of hyperammonemia as neonates. High level gene transfer in newborn mice and monkeys is acheivable, however, it diminishes to low levels due to dilution in the setting of the developing newborn liver. We also have concerns about T cell responses to some neonatal onset subjects since they may have null alleles that fail to delete T cells reactive to the normal version of OTC. Finally, some newborns will have pre-existing immunity to AAVS due to passive transfer of maternal antibodies. Project I will address issues related to T cell responses to transgene-encoded OTC and will attempt to engineer the vector genome to allow for replication when the target cell population is proliferating. Project II will evaluate novel pharmacologic interventions that could augment the efficacy of gene therapy that is less than curative. Project III will engineer the AAVS capsid to escape some level of pre-existing neutralizing antibodies. These Projects will be supported by Core laboratories that specialize in Vector, Cell Morphology and Animal Models. The deliverable at the end of the renewal application is a second generation Clinical Candidate which, in the setting of adjuvant pharmacologic therapy, is suitable for evaluation in humans with neonatal onset OTCD.