ENHANCING PEPTIDE DELIVERY TO THE BRAIN

描述(申请人提供)：创伤性脑损伤(TBI)是美国主要的死亡和残疾原因，发病率为150万，每年花费563亿美元。创伤性脑损伤没有治疗方法，对这种规模的公共卫生问题缺乏治疗干预构成了医疗危机。我们已经开发出一种在小鼠脑损伤后30分钟给药具有神经保护作用的多肽COG133，并证明了COG133与多种蛋白转导结构域(PTD-促进货物在细胞内传递的短碱性多肽)的结合将治疗脑损伤的治疗窗口(TW，即能够显示神经保护的损伤治疗间隔)扩大了四倍，从30分钟增加到120分钟。 具体目的1：测定antpCOG133和synB3COG133在正常小鼠体内的最大耐受量(MTD)；具体目的2：确定治疗窗的剂量和长度(120、180、240和300分钟)对antpCOG133和synB3COG133治疗脑外伤小鼠疗效的影响；具体目的3：采用液-质联用法(LC/MS)测定antpCOG133和synB3COG133静脉注射后多个时间点在小鼠血和脑中的药代动力学和药效学参数；具体目标4：由于脑血流、代谢、水肿、蛋白水解酶和降解酶活性的变化，脑损伤的病理生理特征和后遗症影响药物向脑的输送。因此，脑损伤对antpCOG133和synB3COG133的血液和脑PK/PD的影响将作为损伤后经过的时间的函数来研究。 在临床相关的神经疾病体内模型中，对PTD-Cargo的PK/PD的全面评估在文献中是缺乏的，这将促进对利用PTD的转导潜力治疗多种神经疾病的临床/治疗效用的总体认识。由于缺乏对每年150万受脑外伤影响的患者的有效治疗干预，这一开发努力证明了将PTDS的治疗潜力转化为临床和市场的努力是合理的。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is the leading cause of death and disability in the US with an incidence rate of 1.5 million at cost of $56.3 billion annually. There is no treatment for TBI, and the lack of therapeutic intervention for a public health issue of this magnitude constitutes a healthcare crisis. We have developed COG133, a peptide that is neuroprotective when administered 30 minutes following TBI in mice, and demonstrated that conjugation of COG133 to a variety of protein transduction domains (PTD- short basic peptides that promote the intracellular delivery of cargo) expanded the therapeutic window (TW, i.e., the injury-treatment interval capable of exhibiting neuroprotection) for the treatment of TBI four-fold, from 30 min to 120 min. Specific Aim 1: Determine the maximum tolerated dose (MTD) of antpCOG133 and synB3COG133 in intact mice; Specific Aim 2: Determine the effect of dose and length of the therapeutic window (120, 180, 240, and 300 minutes) on the efficacy of antpCOG133 and synB3COG133 for the treatment of TBI in mice; Specific Aim 3: Determine the pharmacokinetic and pharmacodynamic (PK/PD) parameters of antpCOG133 and synB3COG133 in the blood and brain of uninjured mice via liquid chromatography/ mass spectrometry (LC/MS) at multiple time points following intravenous administration; Specific Aim 4: The patho-physiological features and sequelae of TBI impact drug delivery to the brain due to changes in cerebral blood flow, metabolism, edema, and changes in proteolytic and degradative enzyme activity. Therefore, the impact of TBI on the blood and brain PK/PD of antpCOG133 and synB3COG133 will be investigated as a function of time elapsed since injury. A comprehensive assessment of the PK/PD of PTD-cargo in a clinically relevant in vivo model of neurological disease is lacking in the literature and will advance the general state of knowledge regarding the clinical/therapeutic utility of harnessing the transduction potential of PTDs for the treatment of numerous neurological disorders. The lack of an effective therapeutic intervention for the 1.5 million patients affected by TBI annually justifies this development effort to translate the therapeutic potential of PTDs to the clinic and to the market.