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

项目总结 对于预防和治疗阿尔茨海默病(AD)的治疗方法有着巨大的需求。成年海马区 神经发生(ANN)对正常的学习和记忆至关重要，但在AD患者中它的作用减弱。在.工作 动物模型已经强调了Ahn在面对AD病理时改善认知的作用。因此， 恢复Ahn已成为AD治疗的一个有吸引力的目标。增强病变大脑中的AHN 被广泛认为是治疗AD和其他疾病状态的一种潜在的治疗方式 以神经发生减少为特征，例如额颞叶痴呆、难治性抑郁症、后 创伤应激障碍和中风。然而，到目前为止，药物开发努力还不够 特异性，在不干扰其他干细胞调节机制的情况下选择性地增加Ahn。在此阶段 I努力，Bolden Treeutics将测试跳过外显子的反义寡核苷酸(ASO)对一种未披露的 靶基因在神经干细胞中表达，增加AHN。这些候选外显子跳过ASO成功跳过 靶区在培养的细胞中表现出良好的特性。我们将使用这些 ASO在野生型和AD小鼠模型中的作用，以评估其对AHN、疾病病理学和认知的影响。 跳过外显子的ASO已成为调节中枢神经系统选择性剪接的有效和安全的试剂。 确定我们候选化合物的体内效力是朝着开发高度靶向的、 安全有效的促进青光眼，改善AD认知的治疗。在这些研究之后， 随着我们的工作，跳过外显子的ASO将准备好进行IND使能实验和快速临床前开发 开发一种安全有效的治疗AD等认知功能障碍的方法 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.