GENE THERAPY FOR ORNITHINE TRANSCARBAMYLASE DEFICIENCY

鸟氨酸氨基转移酶缺乏症(OTCD)是尿素合成中最常见的先天性错误，发病率约为1/40,000。OTCD是一种X连锁疾病，目前还没有有效的治疗方法。本研究的目的是建立一种安全剂量的重组腺病毒治疗成人部分OTCD。这项研究的主要目标是确定我们随后将在疗效对照研究中使用的病毒剂量。我们打算在剂量递增毒性研究中研究患有部分OTCD的男性和女性。由于男性幸存者的稀少，我们预测男性与女性的入学比例为1：2。从2x109颗粒/公斤的最低剂量开始，每种剂量将治疗三名患者。在没有毒性的情况下，随后的1/2对数增加。一剂表达OTC基因的重组腺病毒通过选择性动脉内输注到临床稳定的患有副OTCD的成年人的肝脏右叶。在接下来的5个月里，我们将获取血液和尿液，用于毒性、免疫反应和疗效(代谢校正)的证据研究。在第+8天进行一次经皮肝活检，以确定基因转移的直接证据。此外，自基因注射之日起三年内，每三个月采集一次免疫学血液样本。研究的终止将在存在显著毒性的情况下发生。参与者的确切人数将取决于显示毒性和/或有效性所需的剂量。我们预计这将需要总共6个队列，以1/2的对数增量。主要结果是发展为III级或更高的显着毒性。次要结果将集中在对载体的免疫反应和基因转移的证据以及显著的新陈代谢纠正的证据。到目前为止，已经招募了四组研究参与者。这项研究没有发生严重的不良反应。没有重大的与治疗相关的毒性或与程序相关的毒性，所有参与者都保持良好。在基因转移后48小时内，观察到发烧、背部疼痛和全身不适。此外，在载体输注后的4天内，血小板计数平均下降了55%。虽然这一下降的原因尚未确定，但研究人员尚未发现血小板消耗或弥散性血管内凝血的证据。许多参与者还患上了贫血，很可能是与研究相关的静脉切开术的继发性贫血。

Ornithine transcarbamylase deficiency (OTCD) is the most common inborn error of urea synthesis with an incidence of approximately 1 in 40,000. OTCD is an X-linked disorder for which no effective treatment is yet available. The purpose of this study is to establish a safe dose of recombinant adenovirus to serve as a treatment for adults with partial OTCD. The principal objective of this study is to determine a dose of the virus that we will subsequently utilize in controlled studies of efficacy. We intend to study both males and females with partial OTCD in a dose escalation toxicity study. Due to the paucity of male survivors, we predict an enrollment ration of 1:2 males to females. Three patients will be treated at each dose starting with the lowest dose of 2x109 particles/kg. with subsequent 1/2 log increases in the absence of toxicity. A single dose of a recombinant adenovirus expressing the OTC gene is administered by selective intra-arterial infusion into the right lobe of the liver of clinically stable adults with paratial OTCD. Over the subsequent 5 months we will obtain blood and urine for studies of evidence of toxicity, immune response, and efficacy (metabolic correction). A single percutaneous liver biopsy is performed at Day +8 to determine direct evidence of gene transfer. In addition, blood samples for immunology are collected every three months for three years after the date of gene instillation. Termination of the study will occur in the presence of significant toxicity. The exact number of participants will depend on the number of doses that will be required to show toxicity and/or efficacy. We anticipate this to require a total of 6 cohorts in 1/2 log increments. The primary outcome is the development of Grade III or higher significant toxicity. Secondary outcomes will focus on immune responses to the vector and evidence of gene transfer and evidence of significant metabolic correction. To date four cohorts of study participants have been enrolled. No serious adverse effects have occurred as a result of this study. There have been no significant treatment-related toxicities or procedure-related toxicities, and all participants have remained well. Fever, back pain, and general malaise have been observed within 48 hours of the gene transfer. In addition, platelet counts have dropped by an average of 55% within 4 days of the vector infusion. Though the cause of this decrease has not been determined, the investigators have not found evidence of platelet consumption nor disseminated intravascular coagulation. Many participants have also developed anemia, most likely secondary to the study-related phlebotomy.