Development of a PIKFYVE antisense oligonucleotide treatment for FTD

开发用于 FTD 的 PIKFYVE 反义寡核苷酸治疗方法

• 批准号: 10487547
• 负责人: Samuel V Alworth
• 金额: $ 148.06万
• 依托单位: ACURASTEM, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10487547
• 关键词: Address; Antisense Oligonucleotides; Automobile Driving; Autophagocytosis; Autophagosome; Bacterial Artificial Chromosomes; Biological Markers; Brain; C9ORF72; Chemicals; Complex; DNA Sequence Alteration; Data; Development; Dipeptides; Disease; Dose; Evaluation; Frontotemporal Dementia; Genes; Genetic; Genetic Predisposition to Disease; Government; Human; In Vitro; Individual; Lead; Lipids; Lysosomes; Mediating; Modeling; Mus; Nerve Degeneration; Neuraxis; Neurons; Patients; Peripheral; Persons; Pharmaceutical Preparations; Phase; Phosphotransferases; Population; Production; Rattus; Safety; Spinal Cord; TDP-43 aggregation; Testing; Therapeutic; Therapeutic Index; Toxic effect; Vesicle; Work; analytical method; causal variant; in vivo; inhibitor; knock-down; lead candidate; method development; misfolded protein; mouse model; multicatalytic endopeptidase complex; new therapeutic target; nonhuman primate; novel therapeutic intervention; prevent; protein TDP-43; small molecule; tau Proteins; tau aggregation; trafficking

Development of a PIKFYVE suppressing antisense oligonucleotide treatment for FTD Project Summary Frontotemporal dementia (FTD) is a complex disease that results from many diverse genetic etiologies. There are no drugs that slow the progression of FTD. Although therapeutic strategies that target specific causal mutations (e.g. C9ORF72 ASOs) may prove effective against individual forms of FTD, these approaches cannot address the vast majority of cases that have unknown genetic etiology. Moreover, given the large number of different genes that likely contribute to FTD and the fact that each genetic form is relatively rare, this strategy may be difficult to implement for all cases. Thus, there is a pressing need for new therapeutic strategies that rescue multiple forms of FTD, particularly those with unknown genetic etiologies. 45% of FTD patients display cytosolic aggregates of TDP-43 in cortical neurons, while another 45% harbor tau aggregates. Studies suggest that these neuronal TDP-43 and tau aggregates drive neurodegeneration. Thus, to identify new therapeutic targets for FTD, we used cellular reprogramming to generate induced cortical neurons (iNs) from C9ORF72 FTD patients, who display TDP-43 aggregates, as well as MAPT FTD patients, who harbor tau aggregates. We then performed chemical screens to identify targets that rescue the degeneration of both C9ORF72 and MAPT FTD iNs. Inhibitors of PIKFYVE kinase were among the most potent compounds on both C9ORF72 and MAPT FTD iNs. Antisense oligonucleotide (ASO)-mediated suppression of PIKFYVE confirmed that blocking PIKFYVE activity rescues FTD iN survival. In contrast to small molecules, antisense oligonucleotides (ASOs) provide a facile approach to targeting the CNS because they can be injected directly into the spinal cord, achieve sustained target engagement throughout the CNS, and are less likely to cause peripheral toxicity. Thus, we are pursuing ASO-mediated suppression of PIKFYVE as a therapeutic approach for diverse forms of ALS. We have screened hundreds of human PIKFYVE ASOs and identified ten lead ASOs with potent PIKFYVE knockdown in vitro . We have tested hundreds of human PIKFYVE ASOs and identified three promising leads for development. The objective of this Direct to Phase 2 proposal is to further characterize the efficacy of PIKFYVE suppression, and the safety of the lead ASOs to select a bona fide development candidate for advancement in GLP toxicity studies. Our discovery of secretory autophagy as a therapeutic approach in neurodegeneration is high impact for the field because activating the proteasome and autophagy has had mixed results in neurodegeneration models.

开发用于 FTD 的 PIKFYVE 抑制反义寡核苷酸治疗方法 项目概要 额颞叶痴呆（FTD）是一种复杂的疾病，由多种不同的遗传病因引起。那里 没有药物可以减缓 FTD 的进展。尽管针对特定病因的治疗策略 突变（例如 C9ORF72 ASO）可能被证明对个别形式的 FTD 有效，但这些方法不能 解决绝大多数遗传病因未知的病例。此外，鉴于大量 可能导致 FTD 的不同基因以及每种遗传形式都相对罕见的事实，该策略 可能很难在所有情况下实施。因此，迫切需要新的治疗策略 挽救多种形式的 FTD，特别是那些遗传病因未知的 FTD。 45% 的 FTD 患者在皮质神经元中表现出 TDP-43 胞质聚集物，而另外 45% 的患者则在皮质神经元中表现出 TDP-43 胞质聚集物 tau 聚集体。研究表明，这些神经元 TDP-43 和 tau 蛋白聚集体会导致神经退行性变。因此， 为了确定 FTD 的新治疗靶点，我们使用细胞重编程来产生诱导皮质 来自 C9ORF72 FTD 患者的神经元 (iNs)，显示 TDP-43 聚集体，以及 MAPT FTD 患者， 谁拥有tau蛋白聚集体。然后我们进行化学筛选，以确定挽救退化的目标 C9ORF72 和 MAPT FTD iN 的。 PIKFYVE 激酶抑制剂是最有效的化合物之一 在 C9ORF72 和 MAPT FTD iN 上。反义寡核苷酸 (ASO) 介导的 PIKFYVE 抑制 证实阻断 PIKFYVE 活性可挽救 FTD iN 存活。 与小分子相比，反义寡核苷酸（ASO）提供了一种简单的方法来靶向 CNS 因为它们可以直接注射到脊髓中，因此可以在整个过程中实现持续的目标参与 中枢神经系统，并且不太可能引起外周毒性。因此，我们正在寻求 ASO 介导的抑制 PIKFYVE 作为多种形式的 ALS 的治疗方法。我们已经筛查了数百人 PIKFYVE ASO 并鉴定出 10 种在体外具有有效 PIKFYVE 敲低作用的先导 ASO。我们有 测试了数百个人类 PIKFYVE ASO，并确定了三个有前途的开发线索。这 该直接进入第 2 阶段提案的目标是进一步表征 PIKFYVE 的功效 抑制，以及主要 ASO 的安全性，以选择真正的开发候选者 GLP毒性研究的进展我们发现分泌性自噬作为一种治疗方法 神经退行性疾病对该领域具有重大影响，因为激活蛋白酶体和自噬 在神经退行性变模型中的结果好坏参半。