MLKi Therapy for Cognitive Impairment in Multiple Sclerosis

 描述(申请人提供)：本申请专注于多发性硬化症认知障碍的新疗法，以响应PAR-14-088，这是一种新的直接到第二阶段SBIR赠款机制，旨在加快技术开发和商业化的步伐。我们已经在MS的实验性自身免疫性脑脊髓炎(EAE)认知障碍模型中证明了MLK抑制(MLK)有效地保护海马区突触结构和减少小胶质细胞激活的能力。我们合成并表征了两种不同结构的类药物分子，其中一种将根据其在体内模型中的疗效曲线作为潜在的临床化合物来治疗MS的认知障碍。我们还将获得IND支持的安全性研究数据，以使该化合物能够与临床开发合作。对多发性硬化症认知障碍的新疗法的需求是迫切的，因为目前的疗法虽然在预防复发方面有效，但并不能防止进行性认知障碍，这可能会深刻影响独立性、生活质量和日常生活能力。神经成像研究表明，这些症状主要源于大脑中广泛的灰质退化，进展与复发和局灶性白质炎症无关，而后者是目前免疫抑制药物的靶点。MS灰质小胶质细胞的激活与突触连接的丧失和神经元损伤标志物的增加有关，即使在没有持续复发的情况下，这种激活也可以广泛发生。激活的小胶质细胞除了释放自由基和促炎分子外，还会释放兴奋性神经递质谷氨酸，这些分子可以增强谷氨酸的神经毒性作用。在多发性硬化症患者的研究中，这些分子浓度的增加表明多发性硬化症灰质中存在兴奋性毒性损伤的底物。在MS的体内EAE模型中，我们已经证明，在运动症状开始时，每天两次(10 mg/kg，ip)MLK3抑制剂URMC-099，有效地保护海马区突触结构和减少小胶质细胞的激活，而不影响脊髓损伤引起的运动障碍。URMC-099具有良好的中枢神经系统渗透性和明显的安全性，而MLK3的非常有效的抑制剂不是选择性MLK抑制剂。CLFB-1134也是一种类药物分子，具有良好的中枢神经系统渗透性，是MLK3的高度选择性抑制剂。我们将在我们的体内小鼠EAE模型中确定哪种药物更有效地防止小胶质细胞相关的突触变性。突触成分的定量解剖学评估将被用来回答选择性与非选择性MLK3抑制是否提供更好的疗效。定量的电生理参数将被确定，以确定URMC-099与CLFB-1134治疗是否能更好地恢复海马突触的功能。最有效的化合物将被推出用于临床前数据包，以支持IND申请。全世界有超过230万的多发性硬化症患者，其中70%患有某种认知障碍，多达160万人可能会从这种治疗方法中受益。

 DESCRIPTION (provided by applicant): This application focuses on new therapies for cognitive impairment in multiple sclerosis, in response to PAR- 14-088, a new Direct-to-Phase II SBIR grant mechanism to enhance the pace of technological development and commercialization. We have demonstrated the ability of MLK inhibition (MLKi) to efficaciously protect hippocampal synaptic architecture and reduce microglial activation in an experimental autoimmune encephalomyelitis (EAE) model of cognitive impairment in MS. We have synthesized and characterized, two drug-like molecules with different structures, one of which we will advance as a potential clinical compound for the treatment of cognitive impairment in MS based on its profile of efficacy in our in vivo models. We will also obtain IND supporting safety study data to allow partnering of the compound for clinical development. The need for new therapies for cognitive impairment in MS is urgent, because current therapies, while effective at preventing relapses, do not prevent progressive cognitive deficits that can profoundly impact independence, quality of life and activities of daily living. Neuroimaging studies suggest that these symptoms derive largely from widespread degeneration of gray matter in the brain and progress independently of the relapses and focal white matter inflammation that are the targets of current immunosuppressive drugs. Activation of microglia in MS gray matter, which can occur widely even without ongoing relapses, has been associated with loss of synaptic connections and increases in markers of neuronal injury. Activated microglia release the excitatory neurotransmitter glutamate, in addition to radicals and pro-inflammatory molecules that can augment glutamate's neurotoxic effects. Increased concentrations of these molecules in studies of MS patients suggest a substrate for excitotoxic injury in MS gray matter. In an in vivo EAE model of MS, we have demonstrated that twice daily (10 mg/kg, ip) dosing of the MLK3 inhibitor URMC-099, at the onset of motor symptoms, efficaciously protects hippocampal synaptic architecture and reduces microglial activation, without affecting motor deficits that arise from spinal cord damage. URMC-099, with excellent CNS penetration and apparent safety, while a very potent inhibitor of MLK3 is not a selective MLK inhibitor. CLFB-1134, also a drug like molecule with excellent CNS penetration is a highly selective inhibitor of MLK3. We will identify which agent is more efficacious preventing microglia-associated synaptic degeneration in our in vivo murine EAE model. Quantitative anatomic assessment of synaptic elements will be used to answer whether selective vs. non- selective MLK3 inhibition provides superior efficacy. Quantitative electrophysiologic parameters will be ascertained to determine whether URMC-099 vs. CLFB-1134 treatment provides greater functional restoration of hippocampal synapses. The most efficacious compound will be advanced for a preclinical data package to support IND filing. With over 2.3 million people worldwide living with MS, and up to 70% having some type of cognitive impairment, as many as 1.6 million people may benefit from this therapeutic approach.