Promoting adult hippocampal neurogenesis using antisense oligonucleotides as an Alzheimer's disease therapy

使用反义寡核苷酸促进成人海马神经发生作为阿尔茨海默氏病的治疗

基本信息

批准号：
10484703
负责人：
Anne Valat
金额：
$ 49.76万
依托单位：
BOLDEN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10484703
关键词：
Adult Aging Agrin Alternative Splicing Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Animal Model Antisense Oligonucleotides Binding Proteins Bone Morphogenetic Proteins Brain Diseases Cells Characteristics Chemistry Cognition Confidential Information Cultured Cells Dementia Disease Dose Drug Kinetics Engineering Exhibits Frontotemporal Dementia Hippocampus (Brain)Human Impaired cognition Knock-in Mouse Learning Length Maximum Tolerated Dose Mediating Memory Modality Motor Neurons Mus Neurodegenerative Disorders Neuromuscular Junction Pathology Pathway interactions Patients Pharmacodynamics Phase Post-Traumatic Stress Disorders Reporting Role Safety Shapes Signal Pathway Signal Transduction Signaling Protein Specificity Spinal Muscular Atrophy Stroke TREM2 gene Testing Therapeutic Transcript Validation Wild Type Mouse Work age related aged drug development effective therapy efficacy testing exon skipping experimental study improved in vivo interest lead candidate mouse model nerve stem cell nervous system disorder neurogenesis neuron loss newborn neuron novel novel strategies pre-clinical preclinical development prevent receptor safety study screening stem cells therapeutic target therapeutically effective therapy development treatment-resistant depression

Adult Aging Agrin Alternative Splicing Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Animal Model Antisense Oligonucleotides Binding Proteins Bone Morphogenetic Proteins Brain Diseases Cells Characteristics Chemistry Cognition Confidential Information Cultured Cells Dementia Disease Dose Drug Kinetics Engineering Exhibits Frontotemporal Dementia Hippocampus (Brain)Human Impaired cognition Knock-in Mouse Learning Length Maximum Tolerated Dose Mediating Memory Modality Motor Neurons Mus Neurodegenerative Disorders Neuromuscular Junction Pathology Pathway interactions Patients Pharmacodynamics Phase Post-Traumatic Stress Disorders Reporting Role Safety Shapes Signal Pathway Signal Transduction Signaling Protein Specificity Spinal Muscular Atrophy Stroke TREM2 gene Testing Therapeutic Transcript Validation Wild Type Mouse Work age related aged drug development effective therapy efficacy testing exon skipping experimental study improved in vivo interest lead candidate mouse model nerve stem cell nervous system disorder neurogenesis neuron loss newborn neuron novel novel strategies pre-clinical preclinical development prevent receptor safety study screening stem cells therapeutic target therapeutically effective therapy development treatment-resistant depression

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项目摘要

PROJECT SUMMARY There is an enormous need for therapeutics to prevent and treat Alzheimer's disease (AD). Adult Hippocampal Neurogenesis (AHN) is critical for normal learning and memory, but it declines in patients with AD. Work in animal models has underscored the role of AHN in improving cognition in the face of AD pathology. Thus, restoring AHN has emerged as an attractive target for an AD therapy. Augmenting AHN in the diseased brain is widely considered a potential therapeutic modality for the treatment of AD as well as for other disease states characterized by diminished neurogenesis e.g., frontotemporal dementia, treatment-resistant depression, post traumatic stress disorder, and stroke. However, drug development efforts to date have lacked sufficient specificity to selectively increase AHN without perturbing other stem cell regulatory mechanisms. In this Phase I effort, Bolden Therapeutics will test exon-skipping antisense oligonucleotides (ASOs) against an undisclosed target expressed in neural stem cells to increase AHN. These candidate exon-skipping ASOs successfully skip the target region of interest in cultured cells and demonstrate favorable characteristics. We will use these ASOs in wild-type and AD mouse models to evaluate their effect on AHN, disease pathology, and cognition. Exon-skipping ASOs have emerged as effective and safe agents for regulating alternative splicing in the CNS. Determining in vivo efficacy of our candidate compounds is a critical step towards developing a highly targeted, safe and effective therapeutic for promoting AHN and improving cognition in AD. Following these studies, the exon-skipping ASOs will be ready for IND-enabling experiments and rapid preclinical development as we work towards developing a safe and effective therapy for AD and other disorders of impaired cognition via increasing AHN.

项目摘要需要治疗方法预防和治疗阿尔茨海默氏病（AD）。成人海马神经发生（AHN）对于正常的学习和记忆至关重要，但是AD患者的下降。工作动物模型强调了AHN在面对AD病理学方面的认知方面的作用。因此，恢复AHN已成为广告疗法的有吸引力的靶标。在患病的大脑中增强AHN 被广泛认为是用于治疗AD以及其他疾病状态的潜在治疗方式以神经发生的降低为特征创伤性应激障碍和中风。但是，迄今为止的药物开发工作缺乏足够的特异性以选择性地增加AHN而不会扰动其他干细胞调节机制。在这个阶段我努力，Bolden Therapeutics将对未公开在神经干细胞中表达的靶标增加了AHN。这些候选外显子运动ASOS成功跳过培养细胞感兴趣的目标区域并表现出有利的特征。我们将使用这些野生型和AD小鼠模型中的ASO评估其对AHN，疾病病理和认知的影响。出现外显子的ASO已成为调节中枢神经系统中替代剪接的有效和安全的代理。确定候选化合物的体内功效是开发高度有针对性的，安全有效的治疗方法，可促进AHN和改善AD的认知。遵循这些研究，在我们工作时通过增加，为AD和其他认知受损疾病开发安全有效的疗法安。