GENE THERAPY FOR ORNITHINE TRANSCARBAMYLASE DEFICIENCY

鸟氨酸转氨甲酰酶缺乏症（OTCD）是最常见的先天性尿素合成错误，发病率约为1/40，000。 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。 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毒性研究中研究部分OTCD的男性和女性。 由于男性幸存者的缺乏，我们预测男性与女性的入学比例为1：2。 从最低剂量2x 109颗粒/kg开始，每种剂量将治疗3例患者。随后在没有毒性的情况下增加1/2log。 通过选择性动脉内输注将单剂量的表达OTC基因的重组腺病毒施用到患有旁OTCD的临床稳定成人的肝右叶中。 在随后的5个月内，我们将采集血液和尿液，用于毒性、免疫应答和疗效（代谢校正）证据的研究。 在第+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，在基因滴注日期后的三年内，每三个月收集一次用于免疫学的血液样本。如果存在显著毒性，则终止研究。受试者的确切数量将取决于显示毒性和/或疗效所需的剂量数量。 我们预计这总共需要6个队列，增量为1/2对数。 主要结局是发生III级或更高级别的显著毒性。 次要结果将集中于对载体的免疫应答和基因转移的证据以及显著代谢校正的证据。迄今为止，已招募了四组研究参与者。 本研究未发生严重不良反应。 没有明显的治疗相关毒性或手术相关毒性，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，但研究人员没有发现血小板消耗或弥散性血管内凝血的证据。 许多受试者还出现贫血，很可能继发于研究相关的静脉切开术。

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.