Treatment of Lafora disease with an antibody-enzyme fusion

用抗体-酶融合物治疗拉福拉病

• 批准号: 10704334
• 负责人: Matthew S. Gentry
• 金额: $ 38.13万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704334
• 关键词: Treatment; Lafora; disease; antibody; enzyme

Lafora disease (LD) is a fatal childhood epilepsy and a non-classical glycogen storage disorder with no treatment or cure. Over the last 15 years, we and others have defined the molecular underpinnings of LD that position the field to cure this horrific disease. A hallmark of LD is cytosolic aberrant glycogen-like inclusions known as Lafora bodies (LBs) that accumulate in cells of most tissues, including the brain. Like patients, LD mouse models present with LBs and neurodegeneration. Reduced glycogen synthesis via genetic methods eliminates LB formation and rescues the neurological phenotype in LD mouse models. Thus, a current focus in the field is to decrease LBs with the goal of treating LD. Valerion Therapeutics has engineered a cell delivery platform utilizing antibody fragments allowing their antibody-enzyme fusions (AEFs) to deliver a protein into a myriad of cells. In collaboration with Valerion, we recently identified therapeutic strategies to clear LBs. This involves use of a novel targeting functionality fused to active LB-degrading amylases, called VAL-0417 and VAL-1221. We have completed in vitro proof of concept experiments and found that VAL-0417 and VAL-1221 degrade LBs. Further, in situ experiments demonstrate that they penetrate cells and they are active in cells. Strikingly, we see that intracerebroventricular (ICV) injection of VAL-0417 and VAL-1221 efficiently degrade LBs in LD mouse models, lowering total glucan levels of LD mouse brains to near WT levels. Pompe disease is a classical glycogen storage disease caused by lack of the lysosomal enzyme acid α- glucosidase (GAA) that normally degrades glycogen. Valerion has completed pre-clinical studies with VAL- 1221 and initiated a Phase 1/2 clinical trial. This trail involves IV administration of VAL-1221. However, the current VAL-1221 formulation is not suitable for human ICV injections. Therefore, this proposal will: Specific Aims for the R61 phase of the grant (1 year) Specific Aim 1 – Reformulate VAL-1221 for ICV delivery. A series of go/no-go studies will be performed to optimize the activity and stability of VAL-1221. We will also determine the brain biodistribution, pharmacokinetic (PK), and pharmacodynamic (PD) parameters of ICV VAL-1221. Specific Aims for the R33 phase of the grant (2 years) Specific Aim 2 – Establish the optimal in vivo dosing strategy for ICV VAL-1221. We will perform a dose escalation study to determine the maximum tolerated dose of ICV VAL-1221, along with studies that will assess the duration and frequency of ICV VAL-1221 administration that most efficaciously improves glucan clearance from the brains of Laforin knockout mice that have extensive pathological load, i.e. LBs. We are poised to perform the preclinical research required to translate this therapy into the clinic. Additionally, VAL-1221 is a novel approach with potential beyond LD.

拉福拉病 (LD) 是一种致命的儿童癫痫症和一种非经典糖原储存障碍，不伴有任何症状。 在过去 15 年里，我们和其他人已经定义了 LD 的分子基础。 LD 的一个标志是胞浆中异常的糖原样内含物。 被称为拉福拉小体（LB），在大多数组织的细胞中积聚，包括大脑，就像患者一样，LD。 通过遗传方法出现 LB 和神经变性的小鼠模型。 消除 LB 形成并挽救 LD 小鼠模型的神经表型，因此是当前的焦点。 该领域的主要目标是减少 LB，以治疗 LD。 Valerion Therapeutics 设计了一个利用抗体片段的细胞递送平台，使其能够 我们与 Valerion 合作，利用抗体-酶融合 (AEF) 将蛋白质输送到无数细胞中。 最近确定了清除 LB 的治疗策略，这涉及使用新型靶向功能。 与活性 LB 降解淀粉酶融合，称为 VAL-0417 和 VAL-1221 我们已经完成了体外证明。 概念实验发现 VAL-0417 和 VAL-1221 可以降解 LB。进一步进行原位实验。 令人惊讶的是，我们发现它们能够穿透细胞并且在细胞中活跃。 脑室内 (ICV) 注射 VAL-0417 和 VAL-1221 可有效降解 LD 小鼠的 LB 模型中，将 LD 小鼠大脑的总葡聚糖水平降低至接近 WT 水平。 庞贝病是一种典型的糖原累积病，由溶酶体酸α-缺乏引起 通常降解糖原的葡萄糖苷酶 (GAA) 已完成 VAL- 的临床前研究。 1221 并启动了 1/2 期临床试验，该试验涉及 VAL-1221 的 IV 给药。 目前的 VAL-1221 配方不适合人类 ICV 注射，因此，该提案将： R61 阶段拨款的具体目标（1 年） 具体目标 1 – 重新配制用于 ICV 输送的 VAL-1221 将进行一系列通过/不通过研究。 优化 VAL-1221 的活性和稳定性我们还将确定大脑生物分布， ICV VAL-1221 的药代动力学 (PK) 和药效 (PD) 参数。 R33 阶段拨款的具体目标（2 年） 具体目标 2 – 建立 ICV VAL-1221 的最佳体内给药策略 我们将进行一次给药。 确定 ICV VAL-1221 最大耐受剂量的升级研究，以及将 评估最有效地改善葡聚糖的 ICV VAL-1221 给药持续时间和频率 从具有广泛病理负荷（即 LB）的 Laforin 敲除小鼠的大脑中清除。 我们准备进行将这种疗法转化为临床所需的临床前研究。 此外，VAL-1221 是一种具有超越 LD 潜力的新颖方法。