Phase I/II clinical trial evaluating AAV-mediated gene therapy for a severe paediatric metabolic liver disease: Ornithine Transcarbamylase deficiency

评估 AAV 介导的基因疗法治疗严重儿科代谢性肝病：鸟氨酸转氨甲酰酶缺乏症的 I/II 期临床试验

• 批准号: MR/S019111/1
• 负责人: Paul Gissen
• 金额: $ 506.36万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS019111%2F1
• 关键词: Phase; II; clinical; trial; evaluating

Ornithine transcarbamylase deficiency (OTCD) is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is a key element of the urea cycle, whereby the liver breaks down and removes surplus nitrogen from the body. OTCD patients accumulate nitrogen in the form of excess ammonia (hyperammonemia) in the blood. Ammonia is toxic and patients suffer 'hyperammonaemic decompensations' with symptoms including vomiting, impaired voluntary movement, and progressive lethargy. If left untreated these may progress to coma and life-threatening complications. Symptoms present within a few days of birth of males with severe OTCD. As well as significant risk of mortality, the neurotoxic effects of excess ammonia result in longer-term neurological abnormalities such as intellectual disability, developmental delays, and cerebral palsy. As with milder forms of this disease (which may present later in both male and female children and adults), infants are managed with ammonia-scavenging drugs and dietary intervention, however hyperammonaemic decompensations still occur. Neonatal-onset OTCD patients require liver transplantation (LT) for long-term survival. Whilst LT can be life-saving, opportunity for this intervention remains limited and not without risk of mortality and morbidity. Advances have been made in surgical practices to facilitate access to donor liver tissue, including 'living-donor partial liver grafts' and 'reduced-liver transplantation' whereby infants and children receive a portion of an adult liver. However, both the patient and their family still remain with the challenge of life-long immunosuppression and medical follow-up. European guidelines recommend LT for those patients with severe phenotype, aged between 3 and 12 months as neonatal transplant in such metabolically unstable patients is considered too great a risk. Of 15 paediatric OTCD patients transplanted in the UK this past decade, there were only 4 of this age. All others were over 3 years old and all had long-term neurological impairment. We have developed an Adeno associated virus (AAV)-based gene therapy (AAV-LK03-OTC) to specifically target the liver and restore functional expression of OTC. Our approach encompasses the single administration of gene therapy to OTCD infants to provide immediate normalisation of liver metabolism, thereby reducing acute risk of mortality from hyperammonaemic decompensations. Such treatment would serve as a 'bridge-to-transplant' enabling paediatric patients to continue to grow in a metabolically stable condition until such time that transplantation is possible, also minimising longer-term neurological morbidity associated with hyperammonaemia. Our laboratory experiments have demonstrated the enhanced ability of AAV-LK03-OTC to target liver cells over other AAV, and to elicit elevated expression of functional OTC. We have demonstrated that AAV-LK03-OTC restores liver function in experimental mouse models of this genetic disease and are currently testing the safety of AAV-LK03-OTC in animal studies. Recent success with other viral gene therapies advanced to early clinical trials (e.g. AAV8 for Haemophilia B) and the increased targeting to liver cells (AAV-LK03 >10-fold more transformation of liver cells than AAV8) reinforce confidence in this approach as being safe. We will now translate our pre-clinical findings to conduct a Phase I/II dose-finding clinical trial assessing the safety and efficacy of AAV-LK03-OTC. As children are the OTCD population with greatest unmet need, we aim to recruit 12 paediatric patients in the UK to provide early clinical data for later stage development and commercialisation of this transformative advanced therapy. This project aims to deliver a step-change in the clinical management of paediatric OTCD patients and provide critical gene therapy evidence applicable to many other liver-inherited metabolic diseases.

鸟氨酸经氨基酰基酶缺乏症（OTCD）是一种罕见的X连锁遗传疾病，其特征是完全或部分缺乏鸟氨酸鸟氨酸经钙基酶（OTC）。 OTC是尿素周期的关键要素，肝脏会分解并从体内清除剩余的氮。 OTCD患者以血液中过量的氨（高症）的形式积累氮。氨是有毒的，患者遭受了症状，包括呕吐，自愿运动受损和进行性嗜睡的症状。如果不加以治疗，这些可能会发展为昏迷和威胁生命的并发症。严重OTCD的男性出生后几天内出现症状。除死亡率的显着风险外，过度氨的神经毒性作用导致长期神经异常，例如智力障碍，发育延迟和脑瘫。与这种疾病的温和形式（这种疾病的较轻形式可能在男女儿童和成年人中都存在），婴儿被氨扫除药物和饮食干预进行管理，但是仍然发生了超敏症的失毒。新生儿发作的OTCD患者需要肝移植（LT）才能长期存活。尽管LT可以挽救生命，但这种干预的机会仍然有限，并且并非没有死亡率和发病率的风险。在外科手术实践中取得了进步，以促进进入供体肝组织的机会，包括“生活抑制部分肝脏移植物”和“减少肝移植”，使婴儿和儿童获得一部分成人肝脏。但是，患者及其家人仍然面临着终身免疫抑制和医疗随访的挑战。欧洲指南建议那些患有严重表型患者的LT，在这种代谢不稳定的患者中为新生儿移植3到12个月，年龄在3至12个月之间，被认为是太大的风险。在过去的十年中，在英国移植的15名小儿OTCD患者中，只有4例。所有其他人都超过3岁，所有人都有长期的神经系统障碍。我们已经开发了一种基于Adeno相关的病毒（AAV）基因疗法（AAV-LK03-OTC），以专门针对肝脏并恢复OTC的功能表达。我们的方法涵盖了基因治疗对OTCD婴儿的单一施用，以立即提供肝代谢的归一化，从而降低了超富莫纳症失去死亡的急性死亡率。这种治疗方法将作为“转移到移植的”，使小儿患者能够继续在代谢稳定的疾病中生长，直到可能移植是可能的，也可以最大程度地减少与多肌血症相关的长期神经发病率。我们的实验室实验表明，AAV-LK03-OTC靶向肝细胞而不是其他AAV的能力增强，并引起功能性OTC的升高表达。我们已经证明，AAV-LK03-OTC在该遗传疾病的实验小鼠模型中恢复了肝功能，并且目前正在测试动物研究中AAV-LK03-OTC的安全性。与其他病毒基因疗法的最新成功升至早期临床试验（例如，血友病B）和对肝细胞的靶向增加（AAV-LK03>肝细胞的转化比AAV8多于10倍）增强了对这种方法的信心。现在，我们将转换我们的临床前发现，以进行I/II期剂量调查临床试验，以评估AAV-LK03-OTC的安全性和有效性。由于儿童是最需要未满足的OTCD人群，因此我们旨在在英国招募12名儿科患者，以提供早期的临床数据，以进行这种变革性晚期治疗的后期开发和商业化。该项目旨在在小儿OTCD患者的临床管理方面进行逐步变化，并提供适用于许多其他肝脏息肉代谢疾病的关键基因治疗证据。

项目成果

Three-Country Snapshot of Ornithine Transcarbamylase Deficiency.

• DOI: 10.3390/life12111721
• 发表时间: 2022-10-27
• 期刊: Life (Basel, Switzerland)
• 作者: Seker Yilmaz B;Baruteau J;Arslan N;Aydin HI;Barth M;Bozaci AE;Brassier A;Canda E;Cano A;Chronopoulou E;Connolly GM;Damaj L;Dawson C;Dobbelaere D;Douillard C;Eminoglu FT;Erdol S;Ersoy M;Fang S;Feillet F;Gokcay G;Goksoy E;Gorce M;Inci A;Kadioglu B;Kardas F;Kasapkara CS;Kilic Yildirim G;Kor D;Kose M;Marelli C;Mundy H;O'Sullivan S;Ozturk Hismi B;Ramachandran R;Roubertie A;Sanlilar M;Schiff M;Sreekantam S;Stepien KM;Uzun Unal O;Yildiz Y;Zubarioglu T;Gissen P
• 通讯作者: Gissen P

Genetic Therapy Approaches for Ornithine Transcarbamylase Deficiency.

• DOI: 10.3390/biomedicines11082227
• 发表时间: 2023-08-08
• 期刊: Biomedicines
• 影响因子: 4.7

The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges.

• DOI: 10.3390/genes12111837
• 发表时间: 2021-11-21
• 期刊: Genes
• 影响因子: 3.5
• 作者: Jeyaraj R;Bounford KM;Ruth N;Lloyd C;MacDonald F;Hendriksz CJ;Baumann U;Gissen P;Kelly D
• 通讯作者: Kelly D

Age-Related Seroprevalence of Antibodies Against AAV-LK03 in a UK Population Cohort.

• DOI: 10.1089/hum.2018.098
• 发表时间: 2019-01
• 期刊: Human gene therapy
• 影响因子: 4.2
• 作者: Perocheau DP;Cunningham S;Lee J;Antinao Diaz J;Waddington SN;Gilmour K;Eaglestone S;Lisowski L;Thrasher AJ;Alexander IE;Gissen P;Baruteau J
• 通讯作者: Baruteau J

Urea Cycle Related Amino Acids Measured in Dried Bloodspots Enable Long-Term In Vivo Monitoring and Therapeutic Adjustment.

在干血斑中测量尿素循环相关氨基酸可以实现长期体内监测和治疗调整。

• DOI: 10.3390/metabo9110275
• 发表时间: 2019
• 期刊: Metabolites
• 影响因子: 4.1
• 作者: Baruteau J