Gene Therapy for Urea Cycle Disorders

描述（由申请人提供）：这是一份来自宾夕法尼亚大学和儿童国家医疗中心的申请，旨在更新现有的P01项目的资金，该项目名为“尿素循环障碍的基因治疗”。“我们实现了本P01当前4年周期的主要目标。建立了临床候选载体：从肝特异性TBG启动子表达针对鸟氨酸转氨甲酰酶（OTC）的密码子优化的cDNA的AAV。在与我们的伦理咨询委员会密切磋商后，决定在晚发型但严重OTC缺乏症（OTCD）婴儿的I期临床试验中对临床候选药物进行初步评估。我们将使用与P01竞争性更新分开的机制来资助临床试验。在临床前研究中，我们确定了在考虑对新生儿时出现危及生命的高氨血症发作的重度OTCD患者进行临床试验之前应解决的几个问题。在新生小鼠和猴子中高水平的基因转移是可实现的，然而，由于在发育中的新生肝脏环境中的稀释，它减少到低水平。我们还担心T细胞对某些新生儿发病受试者的反应，因为他们可能具有无效等位基因，无法删除对正常OTC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的反应相关的问题，并将尝试设计载体基因组，以便在靶细胞群增殖时进行复制。项目II将评估新的药理学干预措施，可以提高基因治疗的疗效，这是低于治愈。项目III将设计AAVS衣壳以逃避一定水平的预先存在的中和抗体。这些项目将得到专门研究载体、细胞形态学和动物模型的核心实验室的支持。更新申请结束时的交付物是第二代临床候选药物，在辅助药物治疗的背景下，适用于在新生儿发病OTCD患者中进行评价。

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.