Entrepreneurial development award for a novel Alzheimer's disease therapeutic

美国和全球人口老龄化导致对预防和治疗阿尔茨海默病（AD）的治疗剂的迫切需求。成人海马神经发生（AHN）对正常学习和记忆至关重要，并在AD患者中下降。在动物模型中的工作强调了AHN在面对AD病理学时改善认知的作用。因此，恢复AHN已成为AD治疗的有吸引力的靶点。Bolden Therapeutics发现了一种促进AHN的新途径。至关重要的是，该途径可以通过外显子跳跃反义寡核苷酸（ASO）靶向，这是一种市场上的治疗方式，并且已经成为调节CNS中选择性剪接的有效和安全的治疗方式。Valat博士领导了鉴定几种主要ASO的工作，这些ASO成功地跳过了我们在培养细胞中的目标区域。在第一阶段的工作中，这些ASO将在体内进行测试。我们将评估它们的安全性以及它们促进AHN和改善衰老野生型小鼠（目标1）和具有根深蒂固的AD病理学的小鼠模型（目标2）的认知能力。评估这些候选药物的安全性和有效性是支持这些ASO推进IND实验和快速临床前开发的关键步骤。Valat博士在体外实验的技术和科学管理方面拥有丰富的经验，她在Bolden Therapeutics确定主要ASO的工作证明了这一点。在拟议的工作中，她现在将在指导治疗开发的关键体内临床前阶段中发挥主导作用-这对任何制药公司来说都是关键的一步。Valat博士的创业发展将由三位经验丰富的共同导师指导，他们带来了发现科学的技能和经验，与FDA互动，进行临床试验，照顾病人，创办公司，业务发展，筹款和投资新的科学发现。因此，这个奖项将使她成功地从板凳工作过渡到创业职位。在这种实践经验的同时，Valat博士还将受益于LabCentral的一系列创业和职业发展计划，LabCentral是一家首屈一指的生物技术孵化器，她目前正在执行Bolden的研究，NIH提供的计划，如I-Corps，以及麻省理工学院提供的密集创业发展计划。总的来说，该奖项将补充Valat博士的专业知识，并使她能够提高她作为研究科学家和生物技术行业未来领导者的技能。

The aging population in the US and globally has led to an urgent need for therapeutics to prevent and treat Alzheimer's disease (AD). Adult Hippocampal Neurogenesis (AHN) is critical for normal learning and memory and 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. Bolden Therapeutics has discovered a new pathway to promote AHN. Critically, this pathway can be targeted by exon-skipping antisense oligonucleotides (ASOs), a therapeutic modality that is on the market and has emerged as effective and safe for regulating alternative splicing in the CNS. Dr. Valat led the effort to identify several lead ASOs that successfully skip our target region in cultured cells. In this Phase I effort, these ASOs will be tested in vivo. We will evaluate their safety as well as their ability to promote AHN and improve cognition in aging wild-type mice (Aim 1), and in a mouse model with entrenched AD pathology (Aim 2). Evaluating the safety and efficacy of these candidates is a critical step that would support the advancement of these ASOs to IND-enabling experiments and rapid preclinical development. Dr. Valat has extensive experience in the technical and the scientific management of in vitro experiments, as proven by the work that she has done at Bolden Therapeutics in identifying the lead ASOs. In the work proposed she will now take a leading role in directing the key in vivo preclinical phase of therapeutic development - a critical step for any pharmaceutical company. Dr. Valat's entrepreneurial development will be guided by three seasoned co- mentors who bring skills and experience in discovery science, interacting with the FDA, conducting clinical trials, caring for patients, starting companies, business development, fundraising, and investing in novel scientific discoveries. Thus, this award will allow her to transition with success from bench work to an entrepreneurial position. In parallel to this hands-on experience, Dr. Valat will also benefit from a range entrepreneurship and career development programs from LabCentral, a premier biotech incubator where she is currently performing Bolden's research, programs offered by the NIH such as I-Corps, and from an intensive Entrepreneurship Development Program offered at MIT. Overall, this award will complement Dr. Valat's expertise and enable her to advance her skillsets both as a research scientist and as a future leader in the biotechnology industry.