MLKi Therapy for Cognitive Impairment in Multiple Sclerosis

 描述（由申请人提供）：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，这是一种新的直接进入II期SBIR资助机制，旨在加快技术开发和商业化的步伐。我们已经证明了MLK抑制（MLKi）在MS中认知障碍的实验性自身免疫性脑脊髓炎（EAE）模型中有效保护海马突触结构和减少小胶质细胞活化的能力。我们合成并表征了两种具有不同结构的药物样分子，其中之一，我们将基于其在我们的体内模型中的功效概况，将其作为治疗MS中认知障碍的潜在临床化合物。我们还将获得IND支持性安全性研究数据，以便与该化合物合作进行临床开发。迫切需要针对MS认知障碍的新疗法，因为目前的疗法虽然能有效预防复发，但不能预防进行性认知缺陷，这可能会深刻影响独立性、生活质量和日常生活活动。神经影像学研究表明，这些症状很大程度上源于大脑中灰质的广泛变性，并且独立于复发和局灶性白色炎症（当前免疫抑制药物的靶点）而进展。MS灰质中的小胶质细胞的激活，即使没有持续的复发也可以广泛发生，与突触连接的丧失和神经元损伤标志物的增加有关。激活的小胶质细胞释放兴奋性神经递质谷氨酸，除了自由基和促炎分子，可以增加谷氨酸的神经毒性作用。在MS患者的研究中，这些分子的浓度增加表明MS灰质中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发作时每天两次（10 mg/kg，ip）给予MLK 3抑制剂URMC-099有效地保护海马突触结构并减少小胶质细胞活化，而不影响由脊髓损伤引起的运动缺陷。URMC-099具有优异的CNS渗透性和明显的安全性，而MLK 3的非常有效的抑制剂不是选择性MLK抑制剂。CLFB-1134也是一种具有优异CNS渗透性的药物样分子，是MLK 3的高度选择性抑制剂。我们将确定哪种药物在我们的体内小鼠EAE模型中更有效地预防小胶质细胞相关的突触变性。突触元件的定量解剖学评估将用于回答选择性与非选择性MLK 3抑制是否提供上级功效。将确定定量电生理参数以确定URMC-099与CLFB-1134治疗是否提供海马突触的更大功能恢复。最有效的化合物将用于临床前数据包，以支持IND申请。全球有超过230万人患有MS，高达70%的人患有某种类型的认知障碍，多达160万人可能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.