ENHANCING PEPTIDE DELIVERY TO THE BRAIN

描述（由申请人提供）：创伤性脑损伤（TBI）是美国死亡和残疾的主要原因，发病率为150万，每年花费563亿美元。TBI没有治疗方法，缺乏对这种规模的公共卫生问题的治疗干预构成了医疗危机。我们已经开发了C 0 G133，一种当在小鼠中TBI后30分钟施用时具有神经保护性的肽，并且证明了C 0 G133与多种蛋白转导结构域（PTD-促进货物的细胞内递送的短碱性肽）的缀合扩大了治疗窗（TW，即，能够表现出神经保护作用的损伤-治疗间隔），用于治疗TBI四倍，从30分钟到120分钟。 具体目标1：确定antpCOG 133和synB 3COG 133在完整小鼠中的最大耐受剂量（MTD）;具体目标2：确定剂量和治疗窗长度的影响（120、180、240和300分钟）对antpCOG 133和synB 3COG 133治疗小鼠TBI的功效的影响;具体目标3：在静脉内给药后的多个时间点，通过液相色谱/质谱法（LC/MS）测定antpCOG 133和synB 3COG 133在未损伤小鼠血液和脑中的药代动力学和药效学（PK/PD）参数;具体目标4：TBI的病理生理学特征和后遗症由于脑血流、代谢、水肿的变化以及蛋白水解和降解酶活性的变化而影响药物递送至脑。因此，将研究TBI对antpCOG 133和synB 3COG 133的血液和脑PK/PD的影响，作为自损伤以来经过的时间的函数。 文献中缺乏对PTD-货物在神经系统疾病的临床相关体内模型中的PK/PD的全面评估，并且将推进关于利用PTD的转导潜力治疗许多神经系统疾病的临床/治疗效用的一般知识状态。每年有150万TBI患者缺乏有效的治疗干预，这证明了将PTD的治疗潜力转化为临床和市场的发展努力是合理的。

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.