AMPA receptor attenuation as a new therapeutic approach for Batten disease

描述（由申请方提供）：幼年型Batten病（幼年神经元蜡样脂褐质沉积症，JNCL）是一种致死性神经退行性疾病，由CLN 3基因突变引起。目前没有具体的治疗方法可以阻止或减缓疾病的进展。Cln 3功能丧失（Cln 3？ex 1 -6）青少年Batten病的小鼠模型表现出人类疾病的许多特征性特征，包括运动协调缺陷。探索可能的原因（S）的运动不协调Cln 3？ex 1 - 6小鼠，我们发现Cln 3？在分离培养物和器官型小脑切片培养物中的ex 1 -6小脑颗粒细胞比它们的野生型对应物对AMPA型而非NMDA型谷氨酸受体介导的毒性显著更敏感（Kovacs等，2006），表明AMPA受体活性异常增强。衰减AMPA受体活性在一个月大的Cln 3？ex 1 -6小鼠通过单次腹膜内注射特异性AMPA拮抗剂EGIS-8332，导致其运动技能的立即改善，证实异常增加的AMPA受体活性有助于疾病早期的运动协调缺陷。在疾病的后期，在6-7个月大的Cln 3？ex 1 -6小鼠中，EGIS-8332对AMPA受体的急性抑制没有立即作用。相反，它诱导了运动学习的延迟增强和运动技能的长期改善。这些结果表明，暂时抑制AMPA受体可以诱导一个长期持久的纠正预先存在的异常多巴胺能神经传递在体内的青少年Batten病。我们在体内研究中使用的非竞争性AMPA受体拮抗剂EGIS-8332尚未在人体中试用，其所有者是一家小型制药公司（EGIS Pharmaceuticals Plc.）出于财务原因，没有计划使用EGIS-8332进行任何临床试验。然而，诺华公司有一种具有竞争力的AMPA受体拮抗剂NVP-AMP 397，在临床I期试验中发现对人类安全，目前正处于临床II期试验中，作为癫痫的治疗。本提案的目的是测试NVP-AMP 397（诺华公司的慷慨礼物）在Cln 3？ex 1 -6小鼠模型，并提供临床前药理学数据，支持NVP-AMP 397在青少年巴滕病患者中的即时临床试验。 公共卫生相关性： 急性和慢性治疗与NVP-AMP 397在Cln 3？ex 1 -6小鼠强烈支持在青少年Batten病患者中使用这种AMPA受体拮抗剂进行临床试验。

DESCRIPTION (provided by applicant): The juvenile onset form of Batten disease (Juvenile Neuronal Ceroid Lipofuscinosis, JNCL), a fatal neurodegenerative disorder, results from mutations in the CLN3 gene. No specific treatment is currently available that could halt or slow the progression of the disease. The Cln3-loss-of-function (Cln3 ?ex1-6) mouse model of juvenile Batten disease exhibits many characteristic features of the human disorder including a deficit in motor coordination. Exploring the possible cause(s) of the motor incoordination in Cln3 ?ex1-6mice , we have found that Cln3?ex1-6 cerebellar granule cells in dissociated cultures and in organotypic cerebellar slice cultures are significantly more sensitive to AMPA-type, but not NMDA-type, glutamate receptor-mediated toxicity than their wild type counterparts (Kovacs et al., 2006), indicating an abnormally enhanced AMPA receptor activity. Attenuation of AMPA receptor activity in one-month-old Cln3 ?ex1-6 mice by a single intraperitoneal injection of the specific AMPA antagonist, EGIS-8332, resulted in an immediate improvement of their motor skills confirming that an abnormally increased AMPA receptor activity contributes to the motor coordination deficit at this early stage of the disease. At a later stage of the disease, in 6-7-month-old Cln3 ?ex1-6 mice, acute inhibition of AMPA receptors by EGIS-8332 did not have an immediate effect. Instead, it induced a delayed enhancement of motor learning and a long-lasting improvement of motor skills. These results suggest that temporary inhibition of AMPA receptors can induce a long-lasting correction of the pre-existing abnormal glutamatergic neurotransmission in vivo for juvenile Batten disease. The non-competitive AMPA receptor antagonist, EGIS-8332, we used in our in vivo studies, has not been tried in humans, and its owner, a small pharmaceutical company (EGIS Pharmaceuticals Plc.) does not plan any clinical trials with EGIS-8332 for financial reasons. Novartis, however, has a competitive AMPA receptor antagonist, NVP-AMP397, that was found safe in humans in clinical phase I testing and it is now in clinical phase II trials as a treatment for epilepsy. The goal of this proposal is to test the therapeutic efficiency of NVP-AMP397 (a generous gift of Novartis) in the Cln3 ?ex1-6 mouse model of juvenile Batten disease and provide preclinical pharmacological data that would support an immediate clinical trial with NVP-AMP397 in patients with juvenile Batten disease. PUBLIC HEALTH RELEVANCE: A beneficial effect of acute and chronic treatment with NVP-AMP397 in Cln3 ?ex1-6 mice would strongly argue for and support a clinical trial with this AMPA receptor antagonist in patients with juvenile Batten disease.