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.

开发抑制反义寡核苷酸治疗FTD的pikfyve 项目摘要 额颞痴呆（FTD）是一种复杂的疾病，它是由许多不同遗传病因引起的。那里 没有减慢FTD进展的药物。尽管针对特定因果的治疗策略 突变（例如C9ORF72 ASOS）可能证明对单个FTD的单个形式有效，这些方法不能 解决绝大多数遗传病因的情况。而且，考虑到大量 可能导致FTD的不同基因以及每种遗传形式相对罕见的事实，该策略 在所有情况下可能难以实施。因此，迫切需要对新的治疗策略 营救多种形式的FTD，尤其是那些遗传病因未知的FTD。 45％的FTD患者在皮质神经元中显示TDP-43的胞质聚集体，而另外45％的港口 tau聚集。研究表明，这些神经元TDP-43和TAU聚集体驱动神经退行性。因此， 为了识别FTD的新治疗靶标，我们使用细胞重编程来生成诱导的皮质 C9orf72 FTD患者的神经元（INS），显示TDP-43骨料以及MAPT FTD患者， 谁藏有tau聚合。然后，我们进行了化学屏幕以识别拯救退化的目标 C9orf72和Mapt Ftd ins。 Pikfyve激酶的抑制剂是最有效的化合物之一 在C9ORF72和MAPT FTD INS上。反义寡核苷酸（ASO）介导的pikfyve抑制 确认阻塞Pikfyve活动在生存中挽救了FTD。 与小分子相反，反义寡核苷酸（ASO）为靶向靶向 CNS是因为可以将它们直接注入脊髓，请在整个过程中实现持续的目标参与 中枢神经系统，不太可能引起外围毒性。因此，我们正在追求ASO介导的抑制 Pikfyve是一种用于不同形式的ALS的治疗方法。我们已经筛选了数百人 Pikfyve ASOS并在体外鉴定出具有有效的Pikfyve敲低的十个铅ASO。我们有 测试了数百个人类Pikfyve ASO，并确定了三个有希望的发展线索。这 直接向第2阶段提案的目的是进一步表征Pikfyve的功效 抑制和铅ASO的安全性选择一个真正的开发候选人 GLP毒性研究的进步。我们发现分泌自噬是一种治疗方法 神经变性对该领域具有很高的影响，因为激活蛋白酶体和自噬 神经退行性模型的结果混合了。