GENE THERAPY FOR ORNITHINE TRANSCARBAMYLASE DEFICIENCY

鸟氨酸转氨基甲酰基酶缺乏症（OTCD）是最常见的先天性尿素合成错误，发病率约为1 / 40000。OTCD是一种x连锁疾病，目前尚无有效的治疗方法。本研究的目的是建立一个安全剂量的重组腺病毒，作为治疗成人部分OTCD的方法。本研究的主要目的是确定我们随后将用于疗效对照研究的病毒剂量。我们打算在剂量递增的毒性研究中研究患有部分OTCD的男性和女性。由于男性幸存者的缺乏，我们预测男女入学比例为1:2。每个剂量治疗3名患者，最低剂量为2 × 109颗粒/kg。在没有毒性的情况下增加1/2 log。将表达OTC基因的重组腺病毒单剂量选择性动脉内注射到临床稳定的部分性OTCD成人肝脏右叶。在随后的5个月里，我们将获得血液和尿液，以研究毒性、免疫反应和疗效（代谢纠正）的证据。第8天进行单次经皮肝活检以确定基因转移的直接证据。此外，从基因注入之日起的三年内，每三个月采集一次免疫学血样。如果存在明显的毒性，则终止研究。参与者的确切人数将取决于显示毒性和/或疗效所需的剂量。我们预计总共需要6个队列，增量为1/2对数。主要结局是出现III级或更高的显著毒性。次要结果将集中于对载体的免疫反应、基因转移的证据和显著代谢纠正的证据。迄今为止，已有四组研究参与者入组。本研究未发生严重的不良反应。没有明显的治疗相关的毒性或手术相关的毒性，所有参与者都保持良好。在基因转移后48小时内观察到发热、背痛和全身不适。此外，血小板计数在载体输注后4天内平均下降了55%。虽然这种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。许多参与者还出现了贫血，很可能是研究相关的静脉切开术引起的。

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 infustion 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 deccrease 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.