A Safety and Efficacy Study of AAV2-hAADC for AADC Deficiency

AAV2-hAADC 治疗 AADC 缺乏症的安全性和有效性研究

• 批准号: 10505606
• 负责人: Krystof S Bankiewicz
• 金额: $ 347.01万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10505606
• 关键词: 4 year old; Age; Amino Acids; Anesthesia procedures; Aromatic-L-Amino-Acid Decarboxylases; Bilateral; Biological Markers; Biological Products; Brain; California; Cannulas; Carboxy-Lyases; Childhood; Chronic; Clinical; Clinical Trials; Control Groups; Convection; Corpus striatum structure; Data; Developmental Delay Disorders; Diagnosis; Disease; Disorder of neurometabolic regulation; Dopamine; Dose; Dyskinetic syndrome; Dystonia; Enrollment; Enzymes; Epinephrine; Ethics Committees; Exhibits; Family; Funding; Future; Gene Transfer; Genes; Genetic; Goals; Head; Human; Individual; Infusion procedures; Intellectual functioning disability; Involuntary Movements; Lead; Licensing; Magnetic Resonance Imaging; Measures; Medical; Midbrain structure; Moods; Motor; Movement; Multicenter Studies; Muscle; Muscle hypotonia; Mutation; Natural History; Neurologic Dysfunctions; Neurotransmitters; Norepinephrine; Ohio; Operative Surgical Procedures; Outcome; Patients; Pharmaceutical Preparations; Phase; Phase I/II Trial; Physiological; Poland; Positron-Emission Tomography; Procedures; Quality of life; Recombinant adeno-associated virus (rAAV); Recommendation; Research; Research Design; Safety; San Francisco; Serotonin; Side; Signal Transduction; Sleep; Sleep disturbances; Standardization; Structure; Substantia nigra structure; Symptoms; Time; Trust; United States National Institutes of Health; Universities; Ventral Tegmental Area; Waiting Lists; Walking; affective disturbance; aged; amino acid therapy; aromatic L-amino acid decarboxylase deficiency; brain metabolism; clinical efficacy; cohort; disability; disabling symptom; dopaminergic neuron; efficacy study; gene replacement; gene therapy; improved; nervous system disorder; novel; open label; overtreatment; pars compacta; patient advocacy group; programs; prospective; rare genetic disorder; recruit; restoration; safety and feasibility; safety assessment; safety study; uptake; vector

The goal of this proposal is to further evaluate the safety and feasibility of gene transfer to provide aromatic L- amino acid decarboxylase (AADC) enzyme into the midbrain of patients with AADC deficiency and continue Biologics License Application (BLA)-enabling studies as per FDA recommendations. AADC deficiency is a devastating genetic neurometabolic disorder which causes hypotonia, dystonia, intense and long-lasting oculogyric crises (OGC), developmental delay and chronic and severe neurological dysfunction. A gene therapy based on delivering of a recombinant adeno-associated virus carrying the DDC human gene (AAV2-AADC) to the brain structures that physiologically AADC enzyme (midbrain) could be a most needed disease-modifying treatment for AADC deficiency. Eight (8) AADC deficient patients have been treated (160 µL) in our initial NIH- funded trial in the US under BB-IND-16127 and an additional 15 subjects under an ethics committee-approved compassionate use program (CUP) in Poland. The latter received a larger infusion volume (≤300 μL) and a shorter surgical procedure. Both approaches were safe and well-tolerated regardless of dose or volume of infusion. OGCs stopped a few weeks after the surgery and subjects’ sleep, mood and irritability improved. Most subjects are gaining head control and muscular tone, developing purposeful movements and some are even sitting up and starting to walk without support, regardless of their age. Encouraged by the safety and positive biomarker and clinical outcomes observed in those groups, we propose an extension of the BB-IND-16127 study to (i) determine the long-term (up to 5 years) safety and tolerability of the surgical infusion of already treated subjects (n=8) (ii) determine the safety and tolerability of a larger volume of Cohort 2 vector concentration into the SN/VTA administered via a surgical procedure optimized to increase safety by reducing surgical and anesthesia times (single-cannula insertion per hemisphere) in AADC deficient patients >4 years, and (iii) demonstrate effective restoration of AADC function by measuring CSF neurotransmitter metabolites and changes in brain FDOPA uptake on PET imaging. This will be a multi-center study with subjects to be treated at The Ohio State University and at the University of California San Francisco. As per our discussions with FDA, the study design includes a 12-month lead-in period that will serve as a natural history control group to explore potential efficacy of this novel treatment. Cohorts 3 (4-13 years, n≤12) and 4 (>13 years, n≤12) will then receive a larger infusion volume of AAV2-AADC at the same titer Cohort 2 received (2.6 x 1012 vg/mL; up to 300 μL/hemisphere). Renewal of funding for this trial will enable assessment of the safety and tolerability of an optimized dose and delivery procedure to enhance distribution of AADC expression within the midbrain, which we hypothesize may lead to further clinical improvement. Completion of this exploratory clinical trial will pave the way to registration of this disease-modifying AAV2-hAADC gene therapy for AADC deficiency and future gene therapies for other neurological disorders.

该提案的目标是进一步评估基因转移的安全性和可行性，以向 AADC 缺乏症患者的中脑提供芳香族 L-氨基酸脱羧酶 (AADC)，并根据 FDA 继续进行生物制剂许可申请 (BLA) 支持研究AADC 缺乏症建议。AADC 缺乏症是一种破坏性的遗传性神经代谢疾病，会导致肌张力低下、肌张力障碍、严重且持久的眼科危机 (OGC)、发育迟缓以及慢性严重的神经功能障碍。将携带 DDC 人类基因 (AAV2-AADC) 的重组腺相关病毒递送到生理学上 AADC 酶（中脑）的大脑结构可能是八 (8) 名 AADC 缺陷患者最需要的疾病缓解治疗方法。在美国 NIH 资助的 BB-IND-16127 初步试验中接受了治疗（160 µL），另有 15 名受试者接受了伦理委员会批准的同情使用计划（CUP），后者接受了更大的输注量（≤300 μL）和更短的手术过程，无论手术后几周和受试者停止输注的剂量或体积如何，这两种方法都是安全且耐受性良好的。大多数受试者的头部控制能力和肌肉张力得到改善，有的人甚至可以在没有支撑的情况下坐起来并开始行走，无论其年龄如何，都受到安全性和积极的生物标志物以及观察到的临床结果的鼓舞。在对于这些群体，我们建议扩展 BB-IND-16127 研究，以 (i) 确定已接受治疗的受试者 (n=8) 手术输注的长期（长达 5 年）安全性和耐受性 (ii) 确定在 AADC 中，通过优化的外科手术将较大体积的队列 2 载体浓缩到 SN/VTA 中，以提高安全性，通过减少手术和麻醉时间（每个半球插入单插管）来提高安全性和耐受性缺陷患者 >4 年，以及 (iii) 通过测量 CSF 神经递质代谢物和 PET 成像中大脑 FDOPA 摄取的变化来证明 AADC 功能的有效恢复。这将是一项多中心研究，受试者将在俄亥俄州立大学和俄亥俄州立大学接受治疗。根据我们与 FDA 的讨论，该研究设计包括 12 个月的导入期，该导入期将作为自然史对照组，以探索这种新疗法的潜在疗效。 （4-13 岁，n≤12）和 4（>13 岁，n≤12）将接受更大的 AAV2-AADC 输注量，且与队列 2 接受的滴度相同（2.6 x 1012 vg/mL；最多 300 µL/半球）。对该试验的资助将能够评估优化剂量和给药程序的安全性和耐受性，以增强 AADC 表达在体内的分布。我们开创的中脑可能会导致进一步的临床改善，完成这项探索性临床试验将为注册这种针对 AADC 缺陷的疾病修饰 AAV2-hAADC 基因疗法以及未来针对其他神经系统疾病的基因疗法铺平道路。

项目成果

AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients.

从婴儿期到成年期的 AADC 缺乏症：63 名患者的国际队列的症状和发育结果。

• 发表时间: 2020
• 影响因子: 4.2
• 作者: Pearson, Toni S;Gilbert, Laura;Opladen, Thomas;Garcia;Mastrangelo, Mario;Leuzzi, Vincenzo;Tay, Stacy K H;Sykut;Pons, Roser;Mercimek;Kato, Mitsuhiro;Lücke, Thomas;Oppebøen, Mari;Kurian, Manju
• 通讯作者: Kurian, Manju

Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons.

通过 MR 引导的 AAV2-AADC 直接递送至中脑多巴胺能神经元治疗芳香族 L-氨基酸脱羧酶缺乏症的基因治疗。

• 发表时间: 2021
• 影响因子: 16.6
• 作者: Pearson, Toni S;Gupta, Nalin;San Sebastian, Waldy;Imamura;Viehoever, Amy;Grijalvo;Fay, Alex J;Seth, Neha;Lundy, Shannon M;Seo, Youngho;Pampaloni, Miguel;Hyland, Keith;Smith, Erin;de Oliveira Barbosa, Gardenia;Heathcock
• 通讯作者: Heathcock