AMPA receptor attenuation as a new therapeutic approach for Batten disease

描述（由申请人提供）：Batten病（幼年神经性Ceroid Lipofuscinosis， JNCL）是一种致命的神经退行性疾病，由CLN3基因突变引起。目前还没有特定的治疗方法可以阻止或减缓这种疾病的进展。Cln3-功能丧失(Cln3 ？ex1-6)幼年巴滕病小鼠模型显示出许多人类疾病的特征，包括运动协调缺陷。探讨Cln3中运动不协调的可能原因ex1-6mice，我们发现Cln3？与野生型相比，分离培养和器官型小脑片培养中的ex1-6小脑颗粒细胞对AMPA型谷氨酸受体介导的毒性更敏感，但对nmda型谷氨酸受体介导的毒性不敏感（Kovacs等，2006），这表明AMPA受体活性异常增强。1月龄Cln3 ？通过单次腹腔注射特异性AMPA拮抗剂EGIS-8332， ex1-6小鼠的运动技能立即得到改善，证实了异常增加的AMPA受体活性有助于在疾病的早期阶段出现运动协调缺陷。在疾病的后期，在6-7个月大的cl3 ？在ex1-6小鼠中，EGIS-8332对AMPA受体的急性抑制没有立即的效果。相反，它引起了运动学习的延迟增强和运动技能的持久改善。这些结果表明，暂时抑制AMPA受体可以诱导体内存在的异常谷氨酸能神经传递的长期纠正，以治疗幼年巴顿病。我们在体内研究中使用的非竞争性AMPA受体拮抗剂EGIS-8332尚未在人体中进行试验，其所有者，一家小型制药公司（EGIS Pharmaceuticals Plc.）出于财务原因不计划使用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-AMP397，在临床I期测试中被发现在人体中是安全的，目前正处于临床II期试验中，用于治疗癫痫。该提案的目标是测试NVP-AMP397（诺华公司的慷慨捐赠）在Cln3 ？并提供临床前药理学数据，支持NVP-AMP397在青少年巴顿病患者中的立即临床试验。

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.