An antisense oligonucleotide therapy for KCNT1 based epileptic encephalopathies

项目总结： 婴儿期恶性迁移性部分发作(MMPSI)是一种严重的癫痫性脑病 (Ee)导致难治性癫痫发作和严重发育迟缓。它在早期表现出来 儿童时期感染儿童，并可能对受影响的个人及其家庭产生破坏性影响。突变 一种名为KCNT1的基因与MMPSI有关。KCNT1编码离子通道， 在神经系统中高度表达，调节神经元的兴奋性。目前的治疗方法 以KCNT1为基础的MMPSI包括多种临床上疗效有限的抗癫痫药物。 更重要的是，这些药物并不针对疾病的潜在遗传原因。 然而，反义寡核苷酸(ASO)疗法可能提供一种新的治疗策略 靶向在这种疾病中表达的突变的KCNT1通道。最近的临床演示 ASO对其他遗传性疾病的疗效，如脊髓性肌萎缩和肌肉萎缩 营养不良，已经验证了这种方法，并给患者带来了希望。ASO是矮小的，人工合成的 可被设计为识别和击倒特定基因的修饰遗传物质的延伸 基因产品。ASO药物通过注射直接进入中枢神经系统 进入脊髓周围的液体中。在这个研究计划中，ASO将被设计和 在KCNT1连锁的EES的人体细胞模型中进行测试，目标是击倒KCNT1 基因产品，包括那些含有恶性突变的产品。ASOS将被设计成 评估KCNT1基因多个区域的靶向性，这将使基因评估成为可能 基因敲除与突变的位置无关。疾病模型以前已经被 以电生理筛选为特征，包括患者来源的神经细胞，如 以及对照细胞系，这些细胞系已经过基因工程以表达突变的KCNT1。在一个 研究计划的后续阶段，这一阶段的最终候选ASO将是 在体内模型中进一步优化，并最终开发为基于KCNT1的EES的治疗方法。 最终，拟议的研究将使这一特定人群的KCNT1患者受益 突变，他们遭受毁灭性的癫痫发作和神经缺陷，以及提供 为开发其他以ASO为基础的治疗严重遗传病的疗法提供额外的牵引力。

Project Summary: Malignant Migrating Partial Seizures of Infancy (MMPSI) is a severe epileptic encephalopathy (EE) resulting in intractable seizures and severe developmental delays. It manifests early in childhood and can have devastating impacts on affected individuals and their families. Mutations in a gene called KCNT1 have been associated with MMPSI. KCNT1 encodes an ion channel, highly expressed in the nervous system, that regulates neuronal excitability. Current therapies for KCNT1-based MMPSI include a variety of anti-epileptic drugs with limited efficacies in the clinic. More importantly, these drugs do not target the underlying genetic cause of the disease. Antisense oligonucleotide (ASO) therapies may, however, provide a novel therapeutic strategy for targeting mutant KCNT1 channels expressed in this disorder. Recent clinical demonstrations of ASO efficacy in other genetic diseases, such as spinal muscular atrophy and muscular dystrophy, have validated this approach and given hope to patients. ASOs are short, synthetic stretches of modified genetic material that can be designed to recognize and knockdown specific gene products. ASO drugs are administered directly into the central nervous system by injection into the fluid surrounding the spinal cord. In this research program, ASOs will be designed and tested in human cell-based models of KCNT1-linked EEs with the goal of knocking down KCNT1 gene products, including those containing the malignant mutation. ASOs will be designed to assess targeting of many regions of the KCNT1 gene which would enable evaluation of gene knockdown independent of the location of the mutation. Disease models have been previously characterized by electrophysiological screening and include patient-derived neuronal cells, as well as control cell lines that have been genetically-engineered to express mutant KCNT1. In a subsequent phase of the research program, the final candidate ASOs from this phase will be further optimized in in vivo models and ultimately developed as therapies for KCNT1-based EEs. Ultimately, the proposed research stands to benefit this specific population of patients with KCNT1 mutations, who suffer from devastating seizures and neurological deficits, as well as provide additional traction for the development of other ASO-based therapies for severe genetic diseases.