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

项目摘要 存在对预防和治疗阿尔茨海默病（AD）的治疗剂的巨大需求。成年海马 神经发生（AHN）对于正常的学习和记忆至关重要，但它在AD患者中下降。工作 动物模型已经强调了AHN在面对AD病理学时改善认知的作用。因此，在本发明中， 恢复AHN已经成为AD治疗的有吸引力的目标。在患病的大脑中增强AHN 被广泛认为是治疗AD以及其他疾病状态的潜在治疗方式 其特征在于神经发生减少，额颞叶痴呆，难治性抑郁症，后 创伤应激障碍和中风然而，迄今为止的药物开发努力缺乏足够的 特异性选择性增加AHN而不干扰其他干细胞调节机制。在这个阶段 在努力中，Bolden Therapeutics将测试外显子跳跃反义寡核苷酸（ASO）对一个未公开的 靶向表达于神经干细胞中以增加AHN。这些候选外显子跳跃ASO成功地跳跃了 培养细胞中感兴趣的目标区域，并表现出有利的特性。我们将会用这些 在野生型和AD小鼠模型中观察ASO，以评估其对AHN、疾病病理学和认知的作用。 外显子跳跃ASO已成为调节CNS中选择性剪接的有效且安全的试剂。 确定我们的候选化合物的体内功效是开发高度靶向的， 促进AHN和改善AD认知功能的安全有效的治疗方法。根据这些研究， 外显子跳跃的ASOs将为IND启用实验和快速临床前开发做好准备， 通过增加对AD和其他认知障碍的治疗， 安。

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.