Development of Vasoactive Therapeutic

DESCRIPTION (provided by applicant): Approximately 30,000 patients per year in the US suffer from subarachnoid hemorrhage (SAH). Although SAH represents only 5-10% of strokes, its impact is proportionally much higher because SAH patients are typically younger (mean age is 50 years) than other stroke patients. Nearly half of SAH patients die from either the initial hemorrhage or secondary complications that are caused by SAH-induced vasospasm. The only approved pharmaceutical for SAH-induced vasospasm is the calcium channel antagonist Nimotop (nimodipine). Although Nimotop significantly improves the outcome of surviving patients, it does not alter the incidence or magnitude of vasospasm and does not decrease mortality. Thus, there is a significant unmet clinical need for an agent to address SAH-induced vasospasm. Pharmacologic vasorelaxants, which activate cyclic nucleotide-dependent signaling pathways that converge at the phosphorylation of the small heat shock-related protein HSP20 are largely ineffective for treating SAH. We have recently determined that SAH-induced vasospasm is associated with down regulation of HSP20. This finding may explain why pharmacological vasorelaxants are ineffective in the treatment of SAH-induced vasospasm; the downstream protein effector molecule is not available to be activated. More importantly, we have determined that a single intrathecal injection of the HSP20 phosphopeptide analogue, 24 hours after the SAH, completely inhibits vasospasm. The goal of this Phase II project is to commercially develop a proteomic-based therapeutic to prevent SAH-induced vasospasm by directly injecting analogs of an endogenous relaxing protein (HSP20) in to the cerebrospinal fluid. Proteomic-based approaches deliver proteins/peptides into cells by fusing protein transduction domains (PTDs, "carriers") to biologically active molecules ("cargo"). The Phase I project demonstrated that HSP20 analogs are effective at relaxing smooth muscle from a variety of species in vitro. The specific aims of this proposal are to conduct safety testing of PTD-HSP20 analogs in vivo prior to advancement into phase I clinical trials. Since there is currently no effective agent for the treatment of SAH-induced vasospasm, this proteomic treatment would have significant therapeutic potential. This product utilizes a "post-genomic" platform for engineering biologically active protein/peptide molecules and has the potential to be the first proteomic-based pharmaceutical.