Promoting recovery after spinal cord injury with a targeted small molecule

用靶向小分子促进脊髓损伤后的恢复

• 批准号: 7767660
• 负责人: ANTHONY PETER YOUNG
• 金额: $ 16.24万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7767660
• 关键词: Adult; Adverse effects; Affect; Antibodies; Apoptosis; Apoptotic; Attenuated; Behavior; Behavioral; Binding; Biochemical; Biological Assay; Blood - brain barrier anatomy; Brain; Brain-Derived Neurotrophic Factor; Cessation of life; Characteristics; Charge; Clinical Trials; Contusions; Cytochromes; Cytosol; Data; Dose; Esthesia; Event; Exhibits; Goals; Hair; Homeostasis; Human; In Vitro; Infusion procedures; Injection of therapeutic agent; Injury; Intake; Intraperitoneal Injections; Knockout Mice; Ligand Binding; Ligands; MAPK10 gene; Measures; Mechanics; Mediating; Mitochondria; Modeling; Motor; Movement; Mus; NGFR Protein; Neurodegenerative Disorders; Neuroglia; Neurons; Oligodendroglia; Oral; Pain; Peptides; Plasma; Play; Primates; Rattus; Receptor Signaling; Recovery; Recovery of Function; Reporting; Role; Route; Signal Transduction; Site; Spinal Cord; Spinal Ganglia; Spinal cord injury; Swimming; Testing; Therapeutic; Time; Toxic effect; Translating; Walking; Weight; Work; base; behavior test; cold temperature; cytotoxicity; dosage; efficacy testing; functional improvement; improved; in vivo; injured; killings; minimally invasive; novel; painful neuropathy; prevent; receptor; small molecule; success; transcriptional coactivator p75

DESCRIPTION (provided by applicant): For comprehensive functional recovery after spinal cord injury, one must minimize the death of affected neurons and myelinating oligodendrocytes. We have previously reported that a neurotrophin receptor, p75, plays a role in apoptosis of oligodendrocytes after spinal cord injury [7]. As for the ligand that binds and activates the apoptotic cascade of p75 in vivo, we have identified proNGF [8], a novel form of the ligand, which binds p75 selectively [9], and whose expression is upregulated consequent to the injury. Here, our goal is to minimize the loss of oligodendrocytes after injury by blocking p75 activation from the outset, where we disrupt the ability of proNGF to initiate p75-mediated death. As a translational application, an applied goal is to develop an effective and minimally invasive therapeutic strategy with a high likelihood of success in human clinical trials. In this endeavor, we have developed a non-peptide, small molecule, LM11A-31 (C31), that not only blocks proNGF-mediated oligodendrocyte apoptosis in vitro, but also crosses the blood brain barrier when delivered by IV/PO routes or IP injection, providing enormous therapeutic potential. C31 is especially well suited for CNS therapeutics, since the ratio of the compound detected in the brain vs. plasma is greater than 5.0. We thus propose to determine whether C31 is effective at improving functional recovery after spinal cord injury, and determine the optimal dose concentration in terms of maximal improvement without obvious cytotoxicity. Our preliminary data suggest that p75 is one of the receptors involved in cytochrome C release after spinal cord injury. Cytochrome C release into the cytosol represents dysregulation of mitochondrial homeostasis, a hallmark of many pathological conditions. We found that C31 inhibits cytochrome C release that is induced by contusion injury in mice, suggesting that C31 indeed targets p75 in vivo when delivered by IP injection. Our preliminary data also suggest that C31 is not toxic when administered for an extended period of time at 100 mg/kg/day for 4 months and at single dosages of up to 2000 mg/kg in normal adult mice. Even in mice that have undergone contusion injury, C31 is not toxic at 10, 25, and 100 mg/kg, when delivered by IP for 28-42 days, twice daily. We therefore propose to test the efficacy of C31 in a full-scale trial as a way to promote functional recovery of injured mice. Under this goal, we propose to determine the optimal dosage of C31 that promotes motor behavior and coordination without any toxicity for an extended period or significant benefit in pain sensation. Once the optimum dose is determined, we will assess whether oligodendrocyte survival has increased at that concentration.

描述（由申请人提供）： 为了脊髓损伤后的全面功能恢复，必须尽量减少受影响的神经元和髓鞘少突胶质细胞的死亡。我们之前曾报道过神经营养素受体p75在脊髓损伤后少突胶质细胞的凋亡中发挥作用[7]。至于在体内结合并激活p75凋亡级联的配体，我们已经鉴定了proNGF [8]，一种新形式的配体，其选择性结合p75 [9]，并且其表达在损伤后上调。在这里，我们的目标是通过从一开始就阻断p75激活，从而最大限度地减少损伤后少突胶质细胞的损失，在此我们破坏proNGF启动p75介导的死亡的能力。作为一种转化应用，其应用目标是开发一种有效且微创的治疗策略，在人体临床试验中具有很高的成功可能性。在这项奋进中，我们开发了一种非肽小分子LM 11 A-31（C31），其不仅在体外阻断proNGF介导的少突胶质细胞凋亡，而且在通过IV/PO途径或IP注射递送时穿过血脑屏障，提供了巨大的治疗潜力。C31特别适用于CNS治疗，因为在脑与血浆中检测到的化合物的比率大于5.0。因此，我们建议确定C31是否有效地改善脊髓损伤后的功能恢复，并确定最佳剂量浓度的最大改善没有明显的细胞毒性。我们的初步数据表明，p75是参与脊髓损伤后细胞色素C释放的受体之一。细胞色素C释放到胞质溶胶中代表线粒体稳态的失调，这是许多病理状况的标志。我们发现，C31抑制细胞色素C的释放，诱导的挫伤在小鼠中，这表明C31确实靶向p75在体内时，通过IP注射。我们的初步数据还表明，在正常成年小鼠中，当以100 mg/kg/天的剂量长时间给药4个月以及单次给药高达2000 mg/kg时，C31无毒性。即使在遭受挫伤的小鼠中，当通过IP递送28-42天，每天两次时，10、25和100 mg/kg的C31也没有毒性。因此，我们建议在全面试验中测试C31的功效，作为促进受伤小鼠功能恢复的一种方式。在这个目标下，我们建议确定C31的最佳剂量，以促进运动行为和协调，而不会在长时间内产生任何毒性或对疼痛感有显着益处。一旦确定了最佳剂量，我们将评估在该浓度下少突胶质细胞存活率是否增加。