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

• 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
• 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

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.

项目摘要 在这个直接到相的II SBIR中，BioStrategies LC提议提高了新型AAV-的发展 基于粘多糖化的基因疗法IIIA（MPS IIIA，也称为Sanfilippo A综合征）。 与MPS IIIA开发中的其他基因疗法对比，生物制度的方法旨在实现 全身疗法效应，包括在血脑屏障上递送功能替代酶 （BBB）没有胸膜内或室内给药。进一步发展和商业化 BioStrategies的基因疗法有可能提供第一种也是唯一的临床有效治疗 国会议员IIIA，有可能从衰弱的退化效应和早期死亡率造成的患者反应 与这种遗传疾病。它也将作为新的基因治疗方法的强大原则证明 需要将功能性酶传递到中枢神经的其他遗传疾病 除了外围系统。在初步研究中，BioStrategies开发了一种新颖的方法 使用基于AAV的基因疗法将基因输送到中枢神经系统外的肝脏或其他器官 功能性SGSH与无毒的碳水化合物结合亚基B（RTB）相结合，这是一种强烈的讲座 对哺乳动物细胞表面上各种糖蛋白和糖脂的广泛的亲和力。该RTB融合蛋白是 设计用于多次渗透，包括越过BBB以达到大脑中的热水平。 MPS IIIA的动物模型，该SGSH的静脉内给药：RTB融合蛋白可靠，稳健 达到了广泛的分布，包括跨BBB，将硫酸乙酰肝素恢复到大脑的野生型水平 和周围组织。然后，小组证明了针对肝脏的基于AAV的基因疗法 SGSH的连续产生：RTB，大脑中MPS IIIA表型的分布广泛和逆转 和周围组织。在此直接到相的II中，现在的生物制度提出了评估一系列阵列的实用性 优化SGSH的AAV矢量：RTB的生产和分布在体内，然后是强大的，完全供电的效率 在MPS IIIA模型中测试最佳性能AAV构建体。目标1。优化SGSH：RTB产品 设计，翻译效率和安全性。里程碑：根据决策矩阵选择铅候选人 优先考虑最低剂量，最佳安全性和商业化的CNS的最高效率 潜在的（有关研究策略中提供的决策注意事项的全部详细信息）。目标2。评估临床前 基于AAV的SGSH：RTB基因治疗在MPS IIIA小鼠中的功效。里程碑：证明 基于AAV的SGSH静脉注射：RTB基因治疗1）建立不断产生的 SGSH：RTB，2）在大脑和其他感兴趣的器官/组织中实现治疗水平，3）防止进展 与对照组相比，MPS IIIIA表型（即行为，组织病理学，生存）的中，4）在8-- 观察月份和5）延长了寿命。