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

该提案的目标是进一步评估基因转移的安全性和可行性，将芳香L-氨基酸脱羧酶（AADC）酶提供给AADC缺乏症患者的中脑，并根据FDA的建议继续进行生物制剂许可申请（BLA）研究。AADC缺乏症是一种毁灭性的遗传性神经代谢疾病，可导致张力低下、肌张力障碍、强烈和持久的眼神经危象（OGC）、发育迟缓和慢性和严重的神经功能障碍。一种基于将携带DDC人基因（AAV2-AADC）的重组腺相关病毒传递到具有生理AADC酶（中脑）的脑结构的基因治疗可能是AADC缺乏症最需要的疾病改善治疗方法。在美国NIH资助的初始试验中，我们在BB-IND-16127下治疗了8(8)例AADC缺陷患者（160µL），在波兰的伦理委员会批准的同情使用计划（CUP）下治疗了另外15例受试者。后者输注量较大（≤300 μL），手术时间较短。无论输注的剂量或容量如何，这两种方法都是安全且耐受性良好的。ogc在手术后几周停止，受试者的睡眠、情绪和易怒得到改善。大多数受试者的头部控制能力和肌肉张力都有所提高，动作也有了目的性，有些人甚至可以在没有支撑的情况下坐起来走路，无论年龄大小。受这些组中观察到的安全性、阳性生物标志物和临床结果的鼓舞，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）确定通过优化的手术程序将更大容量的队列2载体浓度注入SN/VTA，以通过减少AADC缺陷患者的手术和麻醉时间（每半球单插管）来提高安全性。（iii）通过测量脑脊液神经递质代谢物和PET成像的脑FDOPA摄取变化来证明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加州大学旧金山分校接受治疗。根据我们与FDA的讨论，研究设计包括12个月的导入期，这将作为自然史对照组，以探索这种新疗法的潜在功效。队列3（4-13岁，n≤12）和队列4 （bb0 -13岁，n≤12）在相同滴度下接受更大的AAV2-AADC输注量（2.6 × 1012vg /mL，高达300 μL/半球）。该试验的资金更新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在中脑内的表达分布，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AADC缺乏症的疾病修饰性AAV2-hAADC基因疗法的注册铺平道路，并为其他神经系统疾病的未来基因疗法铺平道路。

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.