Preclinical testing of the splice modulating oligonucleotide LSP-GR1

剪接调节寡核苷酸 LSP-GR1 的临床前测试

• 批准号: 8648831
• 负责人: GORDON J LUTZ
• 金额: $ 75.91万
• 依托单位: LIFESPLICE PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8648831
• 关键词: AMPA Receptors; Alternative Splicing; Amyotrophic Lateral Sclerosis; Antisense Oligonucleotides; Astrocytes; Base Pairing; Behavior; Biodistribution; Blood; Buffers; Cessation of life; Chemistry; Clinical; Clinical Trials; Controlled Study; DNA Damage; Data; Disease; Disease Progression; Dose; Endotoxins; Event; Exons; Exposure to; Glutamate Receptor; Glutamates; Goals; Homo; Infusion procedures; Kinetics; Lead; Longevity; Measures; Mediating; Methods; Molecular Weight; Monkeys; Motor Neuron Disease; Motor Neurons; Mus; Muscular Dystrophies; Neuraxis; Oligonucleotides; Onset of illness; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology and Toxicology; Phase; Preclinical Testing; Property; Protein Isoforms; Quality of life; RNA; RNA Splicing; Rattus; Reading; Reporting; Research; Safety; Small Business Innovation Research Grant; Small Interfering RNA; Spinal Muscular Atrophy; Staging; Structure; Symptoms; Synapses; Techniques; Testing; Time; Tissues; Toxic effect; Toxicogenetics; Toxicokinetics; Toxicology; Variant; base; density; desensitization; design; excitotoxicity; follow-up; improved; in vivo; meetings; mouse model; nervous system disorder; neuromuscular; neuron loss; neurotransmission; novel; phosphorothioate; pre-clinical; programs; public health relevance; receptor expression; research clinical testing; response; safety testing; stability testing; trafficking

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.

描述（由申请人提供）：AMPA谷氨酸受体介导中枢神经系统的大部分快速兴奋性神经传递。存在四种AMPA受体亚基GluA1-GluA4，其功能通道包含这四种亚基的不同组合。AMPA受体表达失调在许多神经系统疾病中都有报道，包括肌萎缩侧索硬化症（ALS），这是一种毁灭性的致命疾病，目前尚无良好的治疗方法。AMPA受体可选择性剪接，最具特征的剪接变体是翻转和翻翻异构体。AMPA受体包含翻转盒与翻翻盒具有不同的通道特性。GluA1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表现出更大的敏感性，增加了突触增益。翻转通道的表达与更容易发生兴奋性毒性和过度兴奋性有关。在ALS患者的运动神经元（MNs）和该疾病的小鼠模型中发现GluA1翻转翻翻比增加。剪接调节寡核苷酸（SMOs）具有独特的化学性质，与传统的反义寡核苷酸和siRNA相比具有明显的优势，目前正在临床试验中用于治疗肌肉萎缩症和脊髓性肌萎缩症。我们已经开发了一种SMO， LSP-GR1，可以在体内特异性和有效地减少GluA1的翻转。在ALS小鼠模型中，LSP-GR1延长寿命并延缓疾病进展。我们II期SBIR的目标是开展IND-临床前药理学/毒理学和CMC研究，为ALS患者的LSP-GR1临床试验奠定基础。GLP药理学/毒理学研究将在大鼠和食蟹猴中进行，以评估其毒性和生物分布。化学、制造和控制（CMC）研究将对LSP- GR1的结构、稳定性和杂质进行评估。这些研究应该会带来ind支持数据，从而允许LSP-GR1在ALS患者中进行临床试验。