Preclinical testing of the splice modulating oligonucleotide LSP-GR1

描述（由申请人提供）：AMPA谷氨酸受体介导中枢神经系统中大部分快速兴奋性神经传递。存在四种AMPA受体亚基，GluA 1-GluA 4，具有含有这四种亚基的各种组合的功能通道。AMPA受体表达的失调已经在许多神经系统疾病中被报道，包括肌萎缩侧索硬化症（ALS），一种没有良好治疗方法的毁灭性和致命性疾病。AMPA受体是可变剪接的，最具特征的剪接变体是翻转异构体。含有翻转盒的AMPA受体具有不同的通道特性。GluA 1翻转和翻转变体具有相似的动力学，但翻转异构体对谷氨酸盐显示出更大的敏感性，增加突触增益。翻转通道的表达与兴奋性毒性和过度兴奋性的更大脆弱性相关。在ALS患者的运动神经元（MN）和该疾病的小鼠模型中发现GluA 1翻转比增加。剪接调节寡核苷酸（SMOs）具有独特的化学性质和优于经典反义寡核苷酸和siRNA的独特优势，并且正在临床试验中用于治疗肌营养不良和脊髓性肌萎缩。我们已经开发了一种SMO，LSP-GR 1，它可以特异性地和有效地减少体内GluA 1翻转。LSP-GR 1在ALS小鼠模型中延长寿命并延缓疾病进展我们的II期SBIR的目标是进行IND-使临床前药理学/毒理学和CMC研究，为ALS患者中LSP-GR 1的临床试验奠定基础。将在大鼠和食蟹猴中进行GLP药理学/毒理学研究，以评价毒性和生物分布。将进行化学、生产和控制（CMC）研究，以评价LSP-GR 1的结构、稳定性和杂质。这些研究应该会产生IND支持数据，使LSP-GR 1能够在ALS患者中进行临床测试。

DESCRIPTION (provided by applicant): AMPA glutamate receptors mediate the majority of fast excitatory neurotransmission in the central nervous system. Four AMPA receptor subunits exist, GluA1-GluA4, with functional channels containing various combinations of these four subunits. Dysregulation of AMPA receptor expression has been reported in many neurological disorders, including amyotrophic lateral sclerosis (ALS), a devastating and fatal disease for which no good treatment exists. AMPA receptors are alternatively spliced, with the best-characterized splice variants being the flip and flop isoforms. AMPA receptors containing flip vs. flop cassettes have distinct channel properties. GluA1 flip and flop variants have similar kinetics but the flip isoform shows greater sensitivity to glutamate, increasing synaptic gain. Expression of flip channels is associated with greater vulnerability to excitotoxicity and hyperexcitability. Increases in GluA1 flip to flop ratio are found in motor neurons (MNs) of ALS patients and in a mouse model of the disease. Splice modulating oligonucleotides (SMOs) have unique chemistries and distinct advantages over classic antisense oligonucleotides and siRNA, and are in clinical trials for treating muscular dystrophy and spinal muscular atrophy. We have developed an SMO, LSP-GR1, that specifically and potently reduces GluA1 flip in vivo. LSP-GR1 increases longevity and delays disease progression in a mouse model of ALS. The goal of our Phase II SBIR is to perform IND- enabling preclinical pharmacology/toxicology and CMC studies to set the stage for clinical testing of LSP-GR1 in ALS patients. GLP pharmacology/toxicology studies will be done in rats and cynomologus monkeys to evaluate toxicity and biodistribution. Chemistry, Manufacturing and Controls (CMC) studies will be done to evaluate structure, stability, and impurities of LSP- GR1. These studies should lead to IND-enabling data to allow LSP-GR1 to move forward to clinical testing in ALS patients.