Gene Therapy that Systemically Produces Brain-penetrating Replacement Enzyme for MPS IIIA (Sanfilippo A Syndrome)

项目摘要 在这个直接进入第二阶段的SBIR中，BioStrategies LC建议推进一种新型AAV的开发， 基于基因治疗的粘多糖沉积症IIIA型（MPS IIIA，也称为Sanfilippo A综合征）。在 与其他正在开发的MPS IIIA基因疗法相比，BioStrategies的方法旨在实现 全身治疗作用，包括递送功能性替代酶穿过血脑屏障 (BBB)而无需鞘内或脑室内施用。进一步开发和商业化 BioStrategies的基因疗法有可能提供第一个也是唯一一个临床有效的治疗方法， MPS IIIA，可能使患者免于衰弱退行性效应和早期死亡相关 遗传性疾病它也将作为一种新的基因治疗方法的强有力的原则证明， 一系列其他遗传性疾病，需要将功能性酶输送到中枢神经系统， 除了外围系统。在初步研究中，BioStrategies开发了一种新方法， 使用基于AAV的基因疗法将基因递送到肝脏或CNS以外的其他器官， 功能性SGSH与蓖麻毒素（RT B）的无毒碳水化合物结合亚单位B结合， 在哺乳动物细胞表面上的糖蛋白和糖脂的广泛阵列的亲和力。该RTB融合蛋白是 设计用于渗透多个组织，包括穿过BBB以在脑中达到治疗水平。在 MPS IIIA动物模型，静脉内给予该SGSH：RTB融合蛋白可靠且稳健 实现了广泛的分布，包括通过BBB，使硫酸乙酰肝素在脑中恢复至野生型水平 和外周组织。研究小组随后证明，靶向肝脏的基于AAV的基因治疗实现了 持续产生SGSH：RTB，在脑中广泛分布并逆转MPS IIIA表型 和外周组织。在这个直接到第二阶段，生物战略现在建议评估一系列的效用， AAV载体优化体内SGSH：RTB的产生和分布，随后产生强大的全功率功效 在MPS IIIA模型中测试表现最好的AAV构建体。目标1。优化SGSH：RTB产品 设计、转染效率和安全性。里程碑：根据决策矩阵选择潜在客户， 优先考虑以最低剂量、最佳安全性特征和商业化在CNS中获得最高疗效 潜力（研究策略中提供的决策考虑因素的全部细节）。目标2.临床前评价 在MPS IIIA小鼠中基于AAV的SGSH：RTB基因疗法的功效。标签：证明一个 静脉内递送的基于AAV的SGSH：RTB基因疗法1）建立了持续产生 SGSH：RTB，2）在脑和其他感兴趣的器官/组织中达到治疗水平，3）防止进展 MPS IIIA表型（即，行为、组织病理学、存活率）与对照组相比，4）在8- 5）延长寿命。

PROJECT SUMMARY In this Direct-to-Phase II SBIR, BioStrategies LC proposes to advance the development of a novel AAV- based gene therapy for mucopolysaccharidosis type IIIA (MPS IIIA, also known as Sanfilippo A syndrome). In contrast to other gene therapies in development for MPS IIIA, BioStrategies’ approach is designed to achieve a systemic therapeutic effect, including delivery of a functional replacement enzyme across the blood brain barrier (BBB) without intrathecal or intraventricular administration. Further development and commercialization of BioStrategies’ gene therapy has the potential to deliver the first and only clinically effective treatment for MPS IIIA, potentially rescuing patients from the debilitating degenerative effects and early mortality associated with this genetic disorder. It would also serve as strong proof-of-principle for a new approach to gene therapy in a broad array of other genetic disorders that require the delivery of functional enzymes to the central nervous system in addition to the periphery. In preliminary studies, BioStrategies developed a novel approach that would use AAV-based gene therapy to deliver genes to the liver or other organs outside of the CNS to produce functional SGSH combined with non-toxic carbohydrate-binding subunit B of ricin (RTB), a lectin that has strong affinity for a broad array of glycoproteins and glycolipids on mammalian cell surfaces. This RTB fusion protein is designed to infiltrate multiple tissues, including crossing the BBB to achieve therapeutic levels in the brain. In animal models of MPS IIIA, intravenous administration of this SGSH:RTB fusion protein reliably and robustly achieved broad distribution, including across the BBB, restoring heparan sulfate to wild-type levels in the brain and peripheral tissues. The team then demonstrated that AAV-based gene therapy targeting the liver achieved continuous production of SGSH:RTB, with broad distribution and reversal of the MPS IIIA phenotype in brain and peripheral tissues. In this Direct-to-Phase II, BioStrategies now proposes to assess the utility of an array of AAV vectors to optimize SGSH:RTB production and distribution in vivo followed by robust, fully-powered efficacy testing of the best performing AAV construct in an MPS IIIA model. Aim 1. Optimize SGSH:RTB product design, transfection efficacy, and safety. Milestone: Select a lead candidate based on a decision matrix that prioritizes the highest efficacy in the CNS with the lowest dose, best safety profile, and commercialization potential (full details on decision considerations provided in the Research Strategy). Aim 2. Evaluate preclinical efficacy of AAV-based SGSH:RTB gene therapy in MPS IIIA mice. Milestones: Demonstrate that an intravenously-delivered AAV-based SGSH:RTB gene therapy 1) establishes continuous production of SGSH:RTB, 2) achieves therapeutic-levels in brain and other organs/tissues of interest, 3) prevents progression of the MPS IIIA phenotype (i.e., behavior, histopathology, survival) compared to controls, 4 ) is safe over an 8- month period of observation, and 5) extends longevity.