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

系统性产生 MPS IIIA（桑菲利波 A 综合征）的脑穿透替代酶的基因疗法

基本信息

批准号：
10760336
负责人：
CAROLE L. CRAMER
金额：
$ 150万
依托单位：
BIOSTRATEGIES, LC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10760336
关键词：
Address Advanced Development Affinity Age Animal Model Antibody Response Behavior Binding Blood - brain barrier anatomy Brain Carbohydrates Caregivers Cell surface Central Nervous System Cessation of life Childhood Chimeric Proteins Clinical Complex Defect Development Disease Dose Enzymes Genes Genetic Genetic Diseases Glycolipids Glycoproteins Heart Heparitin Sulfate Histopathology In Situ In Vitro Infiltration Intrathecal Injections Intravenous Intraventricular Intraventricular Injections Kidney Lectin Life Liver Longevity Lysosomal Storage Diseases Mammalian Cell Methods Modeling Mucopolysaccharidoses Mucopolysaccharidosis III A Mus Musculoskeletal System Nerve Degeneration Organ Other Genetics Pathology Patients Penetration Peripheral Phase Phenotype Price Production Research Ricin Risk Safety Sales Serotyping Small Business Innovation Research Grant Symptoms System Systemic Therapy Teenagers Therapeutic Therapeutic Effect Tissues Transfection adeno-associated viral vector blood-brain barrier crossing commercialization comparison control design design and construction early adolescence effective therapy efficacy evaluation efficacy testing emerging adult enzyme replacement therapy experimental study gene therapy in vivo interest intravenous administration lead candidate manufacturing cost mortality mouse model novel novel strategies preclinical efficacy prevent symptom treatment targeted treatment

项目摘要

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.

项目概要在这个直接进入 II 期 SBIR 中，BioStrategies LC 提议推进新型 AAV-的开发基于基因治疗的 IIIA 型粘多糖贮积症（MPS IIIA，也称为 Sanfilippo A 综合征）。与 MPS IIIA 正在开发的其他基因疗法相比，BioStrategies 的方法旨在实现治疗效果，包括输送功能性替代酶穿过全身血脑屏障（BBB）无需鞘内或心室内给药的进一步开发和商业化。 BioStrategies 的基因疗法有潜力为以下疾病提供第一个也是唯一一个临床有效的治疗方法： MPS IIIA，有可能使患者免受衰弱的退行性影响和相关的早期死亡它也可以作为基因治疗新方法的强有力的原理证明。需要将功能酶输送到中枢神经系统的一系列其他遗传性疾病在初步研究中，BioStrategies 开发了一种新方法，可以使用基于 AAV 的基因疗法将基因传递到肝脏或中枢神经系统以外的其他器官以产生功能性 SGSH 与蓖麻毒素 (RTB) 的无毒碳水化合物结合亚基 B 结合，后者是一种凝集素，具有很强的该 RTB 融合蛋白对哺乳动物细胞表面的多种糖蛋白和糖脂具有亲和力。旨在渗透多个组织，包括穿过血脑屏障以在大脑中达到治疗水平。 MPS IIIA 动物模型，静脉注射该 SGSH:RTB 融合蛋白，可靠且稳健实现了广泛的分布，包括整个血脑屏障，将硫酸乙酰肝素恢复到大脑中的野生型水平研究小组随后证明，基于 AAV 的针对肝脏的基因治疗取得了成功。 SGSH:RTB 的连续产生，在大脑中具有广泛的分布和 MPS IIIA 表型的逆转在直接进入第二阶段中，BioStrategies 现在建议评估一系列的效用。 AAV 载体可优化 SGSH:RTB 体内生产和分布，从而实现强大、全效的功效在 MPS IIIA 模型中测试性能最佳的 AAV 构建体目标 1. 优化 SGSH:RTB 产品。设计、转染功效和安全性：根据决策矩阵选择主要候选药物。优先考虑以最低剂量、最佳安全性和商业化在中枢神经系统中实现最高疗效潜力（研究策略中提供的决策考虑因素的完整细节）。评估临床前。基于 AAV 的 SGSH:RTB 基因治疗对 MPS IIIA 小鼠的疗效里程碑：证明静脉注射基于 AAV 的 SGSH:RTB 基因治疗 1) 建立连续生产 SGSH：RTB，2) 在大脑和其他感兴趣的器官/组织中达到治疗水平，3) 防止进展与对照相比，MPS IIIA 表型（即行为、组织病理学、生存）4）在 8- 一个月的观察期，5) 延长寿命。