ENHANCING PEPTIDE DELIVERY TO THE BRAIN

描述（由申请人提供）：目前有530万美国人因TBI而残疾，每年花费483亿美元。患者、其家庭和社会的经济和社会负担是惊人的，并且目前没有有效的治疗TBI的方法。载脂蛋白E（apoE）受体结合区多肽COG 133在体内外均具有抗炎和神经保护作用。COG 133通过调节神经胶质活化和谷氨酸、活性氧和炎性细胞因子的相关释放以及发挥直接的神经保护作用来减弱中枢神经系统对损伤的反应。当在小鼠中TBI后30分钟施用时，C 0 G133是神经保护性的。与从未完全恢复的盐水处理的小鼠相比，用COG 133处理的小鼠表现出更快的恢复时间和恢复到损伤前水平的行为测试表现。初步数据支持我们的假设，即COG 133的治疗窗口可以通过与蛋白转导结构域（PTD）缀合而扩展超过30分钟。PTD是促进不穿过细胞膜的货物的细胞内递送的短碱性肽。然而，通过血脑屏障（BBB）的转运是一个更复杂的过程，并且在体内测试用于BBB转运的PTD的数量相对较少。因此，需要根据经验确定COG 133转运的适当PTD。1.我们将使用完全随机设计来评估PTD-COG 133缀合物对抑制鼠小胶质细胞BV 2细胞中亚硝酸盐产生的作用。2.我们将使用完全随机设计来评估PTD-COG 133缀合物（将基于体外结果选择3种）和TBI与治疗之间经过的时间对旋转棒评分和体重的影响。目前，还没有确定的神经保护剂可用于治疗TBI。COG 133代表了一种治疗TBI的新治疗策略，从而满足了每年150万持续TBI的美国人未满足的医疗需求。通过与PTD缀合而增强的C 0 G133的递送可以扩大C 0 G133的治疗窗，以及扩大神经障碍的范围以包括缺乏TBI中所见的明显BBB破坏的那些。

DESCRIPTION (provided by applicant): There are currently 5.3 million Americans living with a disability as a result of a TBI, at a cost of $48.3 billion annually. The economic and social burden on the patient, their family, and society, is staggering and there is currently no effective treatment for TBI. COG133, a peptide derived from the receptor-binding region of apolipoprotein E (apoE) has both anti-inflammatory and neuroprotective properties in vitro and in vivo. COG133 attenuates central nervous system response to injury by modulating glial activation and the associated release of glutamate, reactive oxygen species, and inflammatory cytokines, as well as exerting direct neuroprotective effects. COG133 is neuroprotective when administered 30 minutes following TBI in mice. Mice treated with COG133 exhibited faster recovery times and performance on behavioral tests recovered to pre-injury levels, compared to saline treated mice who never fully recovered. Preliminary data supports our hypothesis that the therapeutic window of COG133 can be expanded beyond 30 minutes by conjugation to a protein transduction domain (PTD). PTDs are short basic peptides that promote the intracellular delivery of cargo that does not cross the cell membrane. However, transport through the blood brain barrier (BBB) is a more complex process and the number of PTDs tested for BBB transport in vivo has been relatively few. Therefore, the appropriate PTD for COG133 transport needs to be determined empirically. 1. We will use a completely randomized design to assess the effect of the PTD-COG133 conjugates on suppression of nitrite production in murine microglial BV2 cells. 2. We will use a completely randomized design to assess the effect of PTD-COG133 conjugates (3 will be chosen based on the in vitro results) and time elapsed between TBI and treatment on rotorod score and weight. Currently, there are no definitive neuroprotective agents available to treat TBI. COG133 represents a novel therapeutic strategy for the treatment of TBI, thereby fulfilling an unmet medical need for the 1.5 million Americans who sustain a TBI each year. The enhanced delivery of COG133 by conjugation to a PTD may expand the therapeutic window of COG133, as well as expand the range neurological disorders to include those that lack the overt BBB breach seen in TBI.