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

这项建议的目的是进一步评估基因转移将芳香L氨基酸脱羧酶(AADC)提供给AADC缺乏症患者的安全性和可行性，并按照FDA的建议继续进行生物制品许可证申请(BLA)使能研究。AADC缺乏症是一种严重的遗传性神经代谢紊乱，可导致眼肌张力低下、肌张力障碍、强烈而持久的眼肌危象(OGC)、发育迟缓和慢性严重神经功能障碍。一种基于将携带DDC人类基因的重组腺相关病毒(AAV2-AADC)输送到脑结构的基因疗法，生理上AADC酶(中脑)可能是AADC缺乏症最需要的疾病修正治疗。在我们最初在美国国立卫生研究院资助的试验中，8名ADDC缺陷患者在BB-IND-16127下接受了治疗，在波兰，另外15名受试者在道德委员会批准的慈悲使用计划(CUP)下接受了治疗。后者接受了更大的输液量(≤300μL)和较短的手术程序。这两种方法都是安全和耐受性良好的，无论输液的剂量或体积。OGCs在手术后几周停止，受试者的睡眠、情绪和易怒程度都有所改善。大多数受试者都获得了头部控制和肌肉张力，形成了有目的的动作，有些人甚至坐起来，开始在没有支撑的情况下走路，无论他们的年龄如何。受到在这些组中观察到的安全性和阳性生物标记物和临床结果的鼓舞，我们建议延长BB-IND-16127研究，以(I)确定已经接受治疗的受试者(n=8)手术输注的长期(长达5年)的安全性和耐受性(Ii)确定更大体积的Cohort 2载体浓度进入SN/VTA的安全性和耐受性，通过外科手术程序优化以增加安全性，通过减少手术和麻醉时间(每半球单管插入)在ADC缺乏的患者和GT；通过测量脑脊液神经递质代谢物和PET成像上脑FDOPA摄取的变化，证明AADC功能有效恢复。这将是一项多中心研究，研究对象将在俄亥俄州立大学和加州大学旧金山分校进行。根据我们与FDA的讨论，研究设计包括12个月的引导期，将作为自然病史对照组，以探索这种新疗法的潜在疗效。然后，队列3(4-13年，n≤12)和4(&gt；13年，n≤12)将以与队列2相同的滴度获得更大的AAV2-AADC输液量(2.6x1012Vg/mL；高达300μL/半球)。更新这项试验的资金将能够评估优化的剂量和给药程序的安全性和耐受性，以增强AADC在中脑的分布，我们假设这可能会导致进一步的临床改善。这项探索性临床试验的完成将为这种疾病的注册铺平道路--针对AADC缺乏症的AAV2-hAADC基因疗法以及未来针对其他神经疾病的基因疗法。

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.