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.

Lafora病（LD）是致命的儿童癫痫病，是一种非经典糖原储存障碍，没有 治疗或治愈。在过去的15年中，我们和其他人定义了LD的分子基础 定位该领域以治愈这种可怕的疾病。 LD的标志是胞质异常的糖原样夹杂物 称为Lafora体（LB），它们积聚在包括大脑在内的大多数组织的细胞中。像患者一样，ld 小鼠模型具有LBS和神经变性。通过遗传方法减少糖原合成 消除LB形成并营救LD小鼠模型中的神经表型。那是当前的重点 该领域是通过治疗LD的目标减少LB。 Valerion Therapeutics已经设计了一个使用抗体片段的细胞输送平台 抗体 - 酶融合（AEFS）将蛋白质输送到无数细胞中。在与瓦莱里恩合作的情况下，我们 最近确定了清除LBS的治疗策略。这涉及使用新颖的靶向功能 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降解LBS。此外，原位实验 证明它们穿透细胞并且活跃在细胞中。令人惊讶的是，我们看到了 室内室内（ICV）注射Val-0417和Val-1221在LD小鼠中有效降解LBS 模型，将LD小鼠大脑的总葡聚糖水平降低到接近WT水平。 庞贝病是由于缺乏溶酶体酶α-引起的经典糖原储存疾病 葡萄糖酶（GAA）通常会降解糖原。 Valerion已经完成了通过Val-的临床前研究 1221并开始了1/2期临床试验。这条小径涉及VAL-1221的IV施用。但是， 当前的Val-1221公式不适用于人类ICV注射。因此，该建议将： 赠款的R61阶段的具体目标（1年） 具体目标1 - ICV交付的重新元素-1221。将进行一系列GO/No-Go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）和药效学（PD）参数。 赠款的R33阶段的具体目的（2年） 具体目标2 - 建立ICV Val-1221的最佳体内给药策略。我们将执行剂量 升级研究以确定ICV Val-1221的最大耐受剂量以及将 评估最有效地改善葡聚糖的ICV Val-1221给药的持续时间和频率 Laforin敲除小鼠的大脑清除，具有广泛的病理负荷，即磅。 我们被毒死了将这种疗法转化为诊所所需的临床前研究。 此外，Val-1221是一种新型方法，具有超出LD的潜力。