Commercialization of Selective Dyrk1a Inhibitors for Down Syndrome

项目摘要 唐氏综合征（DS）是由人类21号染色体三体（hsa 21）引起的， 智力和认知残疾的常见遗传形式，每700名活产婴儿中约有1人发生。DS 患者还表现出与年龄相关的进行性认知衰退、神经变性， 在40-50岁时阿尔茨海默病（AD）样病理学的发展。有 目前还没有专门批准用于DS预防认知能力下降的药物， 明确且迫切的未满足的医疗需求。进行性认知能力下降和神经退行性变 与Dyrk 1a（双特异性酪氨酸-（Y）- 磷酸化调节激酶1A），其在所有DS患者中在hsa 21上过表达。鼠标 包括Dyrk 1a过表达的DS模型显示出严重的认知缺陷， 类AD患者的空间学习和运动功能 神经病理学值得注意的是，通过遗传方法使DYRK 1A的基因剂量标准化， DS的Ts 65 Dn模型足以逆转几种神经解剖学AD表型， Dyrk 1a的非选择性小分子抑制剂（CX-4945）能够逆转 Dyrk 1a过表达小鼠的神经退行性表型。这些数据表明，Dyrk 1a 过表达是DS患者表现出的进行性认知下降的关键因素， 是一个有吸引力的治疗靶点。 Iluminos Therapeutics，LLC，（Iluminos）联合创始人Travis Dunckley博士和Christopher博士 Hulme已经开展了持续的药物化学工作（Hulme）和验证策略 （Dunckley）开发和验证选择性和有效的Dyrk 1a抑制剂。在此，我们建议 在I期，以确认我们的先导分子Dyr 533在DS小鼠模型中的疗效。同相 我们建议IND使研究能够推进这种治疗药物的商业化努力。 approach.成功完成拟议短期信托基金的这些阶段， 推进Iluminos的Dyrk 1a战略的商业前景，并可能最终导致 临床试验后，DS患者急需的治疗选择的可用性 随后的几年。

Project Summary Down syndrome (DS) is caused by human chromosome 21 trisomy (hsa21) and is the most common genetic form of intellectual and cognitive disability, occurring in ~1 in 700 live births. DS patients also exhibit age-related progressive cognitive decline, neurodegeneration, and the development of Alzheimer's disease (AD)-like pathology by 40-50 years of age. There are currently no drugs that are approved specifically for DS to prevent cognitive decline, representing a clear and urgent unmet medical need. The progressive cognitive decline and neurodegeneration in DS is strongly linked to the overexpression of Dyrk1a (dual-specificity tyrosine-(Y)- phosphorylation regulated kinase 1A), which is overexpressed on hsa21 in all DS patients. Mouse models of DS that include Dyrk1a overexpression exhibit profound cognitive deficits in hippocampal-dependent spatial learning and motor function associated with AD-like neuropathology. Notably, normalizing the gene dosage of DYRK1A through a genetic method in the Ts65Dn model of DS was sufficient to reverse several neuroanatomical AD phenotypes, and a nonselective small molecule inhibitor of Dyrk1a (CX-4945) was able to reverse neurodegenerative phenotypes in Dyrk1a-overexpressing mice. These data indicate that Dyrk1a overexpression is a key factor in the progressive cognitive decline exhibited by DS patients and is an attractive therapeutic target. Iluminos Therapeutics, LLC, (Iluminos) co-founders Dr. Travis Dunckley and Dr. Christopher Hulme have carried out a sustained medicinal chemistry effort (Hulme) and validation strategy (Dunckley) to develop and validate selective and efficacious Dyrk1a inhibitors. Herein we propose in Phase I to confirm the efficacy of our lead molecule, Dyr533, in a mouse model of DS. In Phase II we propose IND enabling studies to advance the commercialization efforts of this therapeutic approach. Successful completion of these Phases of the proposed STTR will significantly advance the commercial prospects for Iluminos’ Dyrk1a strategy and may ultimately lead to the availability of a much needed therapeutic option for DS patients following clinical trials in subsequent years.