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.

鸟氨酸转氨甲酰酶缺乏症（OTCD）是一种罕见的X-连锁遗传性疾病，其特征是完全或部分缺乏鸟氨酸转氨甲酰酶（OTC）。OTC是尿素循环的关键元素，肝脏通过它分解并从体内清除多余的氮。OTCD患者在血液中以过量氨（高氨血症）的形式积累氮。氨是有毒的，患者会出现“高氨血症失代偿”，症状包括呕吐、自主运动受损和进行性嗜睡。如果不及时治疗，这些可能会发展为昏迷和危及生命的并发症。患有严重OTCD的男性在出生后几天内出现症状。除了显著的死亡风险外，过量氨的神经毒性作用还会导致长期的神经系统异常，如智力残疾、发育迟缓和脑瘫。与这种疾病的轻度形式（可能在男性和女性儿童以及成人中出现）一样，婴儿可以用氨清除药物和饮食干预进行管理，但仍会发生高氨血症失代偿。新生儿发病的OTCD患者需要肝移植（LT）以获得长期生存。虽然LT可以挽救生命，但这种干预的机会仍然有限，并且并非没有死亡和发病的风险。在手术实践中取得了进展，以促进获得供体肝脏组织，包括“活体供体部分肝移植”和“减肝移植”，其中婴儿和儿童接受成人肝脏的一部分。然而，患者及其家属仍然面临终身免疫抑制和医疗随访的挑战。欧洲指南建议对那些具有严重表型的患者进行LT，年龄在3至12个月之间，因为在这种代谢不稳定的患者中进行新生儿移植被认为风险太大。在过去十年中，在英国移植的15名儿童OTCD患者中，只有4名是这个年龄。所有其他人都超过3岁，都有长期的神经功能障碍。我们开发了一种基于腺相关病毒（AAV）的基因治疗（AAV-LK 03-OTC），以特异性靶向肝脏并恢复OTC的功能表达。我们的方法包括对OTCD婴儿进行单次基因治疗，以提供肝脏代谢的立即正常化，从而降低高氨血症失代偿的急性死亡风险。这种治疗将作为“移植的桥梁”，使儿科患者能够在代谢稳定的条件下继续生长，直到移植成为可能，同时也最大限度地减少了与高氨血症相关的长期神经系统发病率。我们的实验室实验已经证明了AAV-LK 03-OTC靶向肝细胞的能力比其他AAV增强，并且引起功能性OTC的表达升高。我们已经证明AAV-LK 03-OTC在这种遗传性疾病的实验小鼠模型中恢复肝功能，目前正在动物研究中测试AAV-LK 03-OTC的安全性。最近其他病毒基因疗法进展到早期临床试验的成功（例如，用于血友病B的AAV 8）和对肝细胞的靶向增加（AAV-LK 03对肝细胞的转化比AAV 8多10倍）增强了对这种方法安全的信心。我们现在将转化我们的临床前研究结果，以进行I/II期剂量探索临床试验，评估AAV-LK 03-OTC的安全性和有效性。由于儿童是OTCD人群中需求最大的人群，我们的目标是在英国招募12名儿科患者，为这种变革性先进疗法的后期开发和商业化提供早期临床数据。该项目旨在为儿科OTCD患者的临床管理提供一个台阶式的变化，并提供适用于许多其他肝脏遗传性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

Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development.

• DOI: 10.3390/biom11040611
• 发表时间: 2021-04-20
• 期刊: Biomolecules
• 影响因子: 5.5
• 作者: Massaro G;Geard AF;Liu W;Coombe-Tennant O;Waddington SN;Baruteau J;Gissen P;Rahim AA
• 通讯作者: Rahim AA