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）是一种致命的儿童癫痫，是一种非经典的糖原储存障碍， 治疗或治愈。在过去的15年里，我们和其他人已经确定了LD的分子基础， 来治疗这种可怕的疾病LD的一个标志是胞浆中异常的糖原样包涵体 Lafora小体（LB），聚集在包括大脑在内的大多数组织的细胞中。像病人一样，LD 小鼠模型表现出LB和神经变性。通过遗传方法减少糖原合成 消除LB形成并挽救LD小鼠模型中的神经表型。因此，目前的焦点 在该领域的目标是减少LBs治疗LD。 Valerion Therapeutics已经设计了一种利用抗体片段的细胞递送平台， 抗体-酶融合体（AEFs）将蛋白质递送到无数细胞中。与Valerion合作，我们 最近确定了清除LB的治疗策略。这涉及到使用一种新的定位功能 与称为瓦尔-0417和瓦尔-1221的活性LB降解淀粉酶融合。我们已经完成了体外证明 概念实验，发现瓦尔-0417和瓦尔-1221降解LB。此外，现场实验 证明它们能穿透细胞并在细胞中活跃。令人惊讶的是，我们看到， 脑室内（ICV）注射瓦尔-0417和瓦尔-1221有效降解LD小鼠中LB 模型，将LD小鼠脑的总葡聚糖水平降低至接近WT水平。 庞贝氏症是一种典型的糖原贮积病，由于缺乏溶酶体酸性酶α- 葡萄糖苷酶（GAA）通常降解糖原。Valerion已完成瓦尔的临床前研究- 1221并启动了1/2期临床试验。该试验涉及瓦尔-1221的IV给药。但 目前的瓦尔-1221制剂不适用于人ICV注射。因此，本提案将： R61阶段赠款的具体目标（1年） 具体目标1 -重新配制瓦尔-1221用于ICV输送。将进行一系列通过/不通过研究， 优化瓦尔-1221的活性和稳定性。我们还将确定大脑的生物分布， ICV瓦尔-1221药代动力学（PK）和药效学（PD）参数。 R33补助金阶段的具体目标（2年） 具体目标2 -确立ICV瓦尔-1221的最佳体内给药策略。我们将进行一次剂量 确定ICV瓦尔-1221最大耐受剂量的递增研究，沿着将 评估ICV瓦尔-1221给药的持续时间和频率，以最有效地改善葡聚糖 从具有广泛病理负荷（即LB）的Laforin敲除小鼠的脑中清除。 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，瓦尔-1221是一种新方法，具有超越LD的潜力。