HUMAN STUDIES OF ORNITHINE TRANSCARBAMYLASE DEFICIENCY

鸟氨酸转氨酶缺乏症的人体研究

• 批准号: 6272338
• 负责人: MARK L. BATSHAW
• 金额: $ 14.13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272338
• 关键词: Adenoviridae; T cell receptor; adult human (21+); ammonia; cell mediated cytotoxicity; child (0-11); clinical trials; cytotoxic T lymphocyte; defective virus; developmental neurobiology; gene expression; gene therapy; genetic transduction; heterozygote; human subject; human therapy evaluation; longitudinal human study; neuropsychological tests; newborn human (0-6 weeks); ornithine carbamoyl phosphate deficiency; ornithine carbamoyltransferase; orotate; transfection /expression vector; urea cycle; virus antigen; virus genetics

We have concluded that ornithine transcarbamylase deficiency (OTCD) is a well suited disease for the development of both acute and long-term gene therapy. Current treatment of OTCD has failed to avert a high mortality or morbidity rate; Given the relative frequency of OTCD, an adequate population is available for study; The OTC gene has been sequenced and preliminary studies of gene therapy in animal models have been promising; The OTC gene is not rate-limiting for ureagenesis, so excessive activity should not have adverse consequences; The disorder is X-linked and hemizygous males have virtually absent enzyme activity; and Restoration of enzyme activity in the liver, should suffice to normalize metabolism without the need to introduce the gene into the central nervous system. We propose to study in vivo gene therapy for OTCD with a recombinant adenovirus in order to control acute, life-threatening hyperammonemic crises. We also propose to use ex vivo transfer of the OTC gene with a recombinant retrovirus to provide long-term management of patients who are clinically stable at the time of gene therapy, but who remain at high risk of sustaining brain damage or of dying because of a future hyperammonemic episode. Stable transduction will also be tested in children using a second generation recombinant adenovirus. Studies will focus on duration of metabolic, neurochemical, toxicologic, and immunologic consequences, and neurodevelopmental outcome. There are three specific aims to this project: (I) We hypothesize that a recombinant adenovirus containing the OTC gene will be effective and safe for the short-term treatment of neonates and older children with OTCD who are in hyperammonemic crisis. To establish the effective and safe dose we will initially test various doses of the construct in adult asymptomatic OTCD heterozygotes. We will subsequently treat neonates in hyperammonemic coma and infants, children and adults with symptomatic OTCD using the recombinant adenovirus. Efficacy will be measured by normalization of plasma ammonium, urea cycle intermediates, and urinary orotate excretion, rate of flux through the urea cycle, and OTC correction in liver. (II) We hypothesize that long-term correction of OTCD can be achieved either by ex vivo or in vivo gene therapy using a recombinant retrovirus or a second generation temperature sensitive recombinant adenovirus. (III) Finally, we hypothesize that immune activation following gene therapy may affect safety, efficacy and duration of gene therapy.

我们得出的结论是，鸟氨酸经氨基甲酸酶缺乏症（OTCD）是 适合急性和长期发展的疾病 基因疗法。当前对OTCD的治疗未能避免高 死亡率或发病率；考虑到OTCD的相对频率 足够的人口可供研究； OTC基因已经 动物模型中基因治疗的测序和初步研究具有 很有希望OTC基因对尿素发生不限制，因此 过度活动不应产生不利的后果；该疾病是 X连锁和半合子的雄性实际上没有酶活性。和 恢复肝脏中的酶活性，应足以正常化 代谢无需将基因引入中心 神经系统。我们建议研究用于OTCD的体内基因治疗 重组腺病毒，以控制急性，威胁生命 高症危机。我们还建议使用OTC的体内转移 具有重组逆转录病毒的基因，可长期管理 基因治疗时临床稳定的患者，但谁 由于脑部损伤或死亡的高风险 未来的高症发作。稳定的转导还将测试 在使用第二代重组腺病毒的儿童中。研究 将专注于代谢，神经化学，毒理学和 免疫后果和神经发育结果。有三个 该项目的具体目的：（i）我们假设是重组 包含OTC基因的腺病毒对 对正在使用的新生儿和年龄较大的OTCD的短期治疗 高症危机。为了建立有效且安全的剂量，我们将 最初在成人无症状OTCD中测试各种剂量的构建体 杂合子。我们随后将在高症昏迷中治疗新生儿 和婴儿，儿童和成人有症状的OTCD使用 重组腺病毒。功效将通过标准化来衡量 血浆铵，尿素循环中间体和尿道排泄， 通过尿素周期的通量速率和肝脏中的OTC校正。 （ii） 我们假设可以实现OTCD的长期校正 通过体内或体内基因治疗使用重组逆转录病毒或A 第二代温度敏感的重组腺病毒。 （iii） 最后，我们假设基因治疗后的免疫激活可能 影响基因治疗的安全性，有效性和持续时间。