MLKi Therapy for Cognitive Impairment in Multiple Sclerosis

MLKi 疗法治疗多发性硬化症认知障碍

• 批准号: 8904155
• 负责人: HARRIS A GELBARD
• 金额: $ 58.67万
• 依托单位: CALIFIA BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904155
• 关键词: Activities of Daily Living; Acute; Affect; Ames Assay; Anatomy; Anti-Inflammatory Agents; Anti-inflammatory; Architecture; Biological Assay; Brain; Canis familiaris; Cardiovascular system; Chromosome abnormality; Clinical; Cognitive; Cognitive deficits; Cyclic GMP; Data; Development; Dose; Drug Formulations; Drug Kinetics; Drug Stability; Elements; Experimental Autoimmune Encephalomyelitis; Glutamates; Grant; HIV-1; Hippocampus (Brain); Human; Immunologics; Immunosuppressive Agents; Impaired cognition; Inflammation; Inflammatory; Injury; Investigational New Drug Application; Learning; Life; Memory; Metabolic; Methods; Microglia; Modeling; Motor; Multiple Sclerosis; Mus; Neuraxis; Neurodegenerative Disorders; Neuronal Injury; Neurotransmitters; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Phase; Phosphotransferases; Physiological; Process; Progressive Disease; Property; Quality of life; Rattus; Relapse; Safety; Sensory; Small Business Innovation Research Grant; Source; Spinal cord damage; Structure; Symptoms; Synapses; Techniques; Testing; Therapeutic; Therapeutic Index; Toxicogenetics; Toxicology; Validation; Wages; base; behavioral study; commercialization; disability; effective therapy; functional restoration; gray matter; in vivo; in vivo Model; indexing; inhibitor/antagonist; manufacturing process; micronucleus; motor deficit; neurocognitive disorder; neuroimaging; neurotoxic; pre-clinical; preclinical safety; prevent; public health relevance; respiratory; response; safety study; safety testing; synaptic function; white matter

 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.

 描述（由申请人提供）：本申请重点关注多发性硬化症认知障碍的新疗法，响应 PAR-14-088，这是一种新的直接二期 SBIR 资助机制，旨在加快技术开发和商业化的步伐。我们在实验性自身免疫性脑脊髓炎中证明了 MLK 抑制 (MLK​​i) 能够有效保护海马突触结构并减少小胶质细胞激活我们合成并表征了两种具有不同结构的药物样分子，其中一种根据其功效，将作为治疗多发性硬化症认知障碍的潜在临床化合物进行开发。我们还将获得支持性安全性研究数据，以便将该化合物用于临床开发，迫切需要针对多发性硬化症认知障碍的新疗法，因为目前的疗法虽然可以有效预防复发，但不能预防复发。进行性认知缺陷会严重影响独立性，神经影像学研究表明，这些症状很大程度上源于大脑灰质的广泛退化，并且与复发和局灶性白质炎症无关，而这些炎症是当前小胶质细胞激活的目标。即使没有持续复发，灰质多发性硬化症也可能广泛发生，除了与突触连接丧失和神经元损伤标记物增加有关外，激活的小胶质细胞还释放兴奋性神经递质谷氨酸。在多发性硬化症患者的研究中，自由基和促炎分子可以增强谷氨酸的神经毒性作用，这表明这些分子是多发性硬化症灰质中兴奋性毒性损伤的底物，我们已经证明，每天两次（在运动症状出现时，以 10 mg/kg（腹腔注射）给药 MLK3 抑制剂 URMC-099，可有效保护海马突触结构并减少小胶质细胞激活，而不影响URMC-099 具有出色的 CNS 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，也是一种具有出色 CNS 渗透性的药物分子。我们将在体内小鼠 EAE 模型中对突触元件进行定量解剖学评估，以确定哪种药物能更有效地预防小胶质细胞相关的突触变性。用于回答选择性与非选择性 MLK3 抑制是否提供更好的功效将确定定量电生理参数，以确定 URMC-099 与 CLFB-1134 治疗是否提供更有效的海马突触功能恢复。全球有超过 230 万人患有 MS，其中高达 70% 的人患有某种类型的认知疾病。多达 160 万人可能会从这种治疗方法中受益。

项目成果

Complement-dependent synapse loss and microgliosis in a mouse model of multiple sclerosis.

多发性硬化症小鼠模型中补体依赖性突触丢失和小胶质细胞增生。

• 发表时间: 2020
• 作者: Hammond, Jennetta W;Bellizzi, Matthew J;Ware, Caroline;Qiu, Wen Q;Saminathan, Priyanka;Li, Herman;Luo, Shaopeiwen;Ma, Stefanie A;Li, Yuanhao;Gelbard, Harris A
• 通讯作者: Gelbard, Harris A