ENHANCING PEPTIDE DELIVERY TO THE BRAIN

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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.