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: 10299327
• 负责人: Krystof S Bankiewicz
• 金额: $ 368.31万
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299327
• 关键词: 4 year old; Age; Amino Acids; Anesthesia procedures; Aromatic-L-Amino-Acid Decarboxylases; Bilateral; Biological; Biological Markers; 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.

本提案的目的是进一步评价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的建议继续进行生物制品许可申请（BLA）启用研究。AADC缺乏症是一种破坏性的遗传性神经代谢障碍，可导致张力减退、肌张力障碍、强烈且持久的眼球转动危象（OGC）、发育迟缓以及慢性和严重的神经功能障碍。基于将携带DDC人基因的重组腺相关病毒（AAV 2-AADC）递送到脑结构的基因治疗，生理学上的AADC酶（中脑）可能是AADC缺乏症最需要的疾病修饰治疗。8例AADC缺乏患者在我们的美国NIH资助的BB-IND-16127初始试验中接受了治疗（160 µL），另外15例受试者在波兰伦理委员会批准的体恤使用项目（CUP）中接受了治疗。后者接受了更大的输注量（≤300 μL）和更短的手术时间。无论输注剂量或体积如何，这两种方法都是安全的，耐受性良好。OGCs在手术后几周停止，受试者的睡眠，情绪和易怒得到改善。大多数受试者正在获得头部控制和肌肉张力，发展有目的的运动，有些人甚至坐起来，开始在没有支撑的情况下行走，无论他们的年龄如何。在这些组中观察到的安全性和积极的生物标志物和临床结果令人鼓舞，我们建议延长BB-IND-16127研究，以（i）确定长期（ii）确定更大体积的队列2载体浓度进入SN/SN的安全性和耐受性，VTA通过外科手术给药，优化了AADC缺陷患者4年以上的手术和麻醉时间（每个半球插入一根插管），以增加安全性，（iii）通过测量CSF神经递质代谢物和PET成像上脑FDOPA摄取的变化，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州立大学和加州大学弗朗西斯科分校接受治疗。根据我们与FDA的讨论，研究设计包括12个月的导入期，将作为自然史对照组，以探索这种新型治疗的潜在疗效。然后，组3（4-13岁，n≤12）和组4（>13岁，n≤12）将以与组2接受的相同滴度（2.6 × 1012 vg/mL;高达300 μL/半球）接受更大输注体积的AAV 2-AADC。本试验的资金更新将能够评估优化剂量和递送程序的安全性和耐受性，以增强AADC表达在中脑内的分布，我们假设这可能导致进一步的临床改善。这项探索性临床试验的完成将为AADC缺陷症的疾病修饰AAV 2-hAADC基因疗法和其他神经系统疾病的未来基因疗法的注册铺平道路。