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Cell permeant peptidomimetics to prevent delayed vasospasm and neurological deficits after subarachnoid hemorrhage

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41NS122656-01A1
Agency Tracking Number: R41NS122656
Amount: $261,863.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 107
Solicitation Number: PA20-265
Solicitation Year: 2020
Award Year: 2022
Award Start Date (Proposal Award Date): 2022-02-01
Award End Date (Contract End Date): 2023-01-31
Small Business Information
2126 21ST AVE S
Nashville, TN 37212-4318
United States
DUNS: 117501993
HUBZone Owned: No
Woman Owned: Yes
Socially and Economically Disadvantaged: No
Principal Investigator
 (615) 321-6350
Business Contact
Phone: (615) 750-2278
Research Institution
1161 21ST AVE SSTE D3300 MCN
NASHVILLE, TN 37232-0011
United States

 Domestic Nonprofit Research Organization

PROJECT SUMMARYSubarachnoid hemorrhage (SAH) due to rupture of an intracranial aneurysm leads to delayed
vasospasm resulting in neuroischemia (stroke). The overall morbidity (profound neurologic deficit in
10-20% of survivors) and mortality (50%) are high, and the disease affects a relatively young adult
population. Therapeutic options to prevent delayed vasospasm and neuroischemia after SAH are
currently limited to hemodynamic optimization and nimodipine, which have marginal clinical efficacy.
Thus, treatment of delayed vasospasm after SAH represents an unmet clinical need in an orphan
population with severe clinical consequences.Attempts to treat SAH-induced vasospasm with existing vasodilators often fail because of systemic
hypotension (leading to decreased cerebral perfusion) and a cerebral vasculature that is refractory to
activation of nitric oxide (NO)-dependent signaling pathways.5 NO signaling modulates vascular
smooth muscle (VSM) relaxation and regulation of cerebral blood flow. The impaired response of
cerebral vessels to vasodilators, i.e. impaired vasorelaxation after SAH, is likely due to down regulation
of the signaling elements in the NO pathway after SAH. The hypothesis of this investigation is that
treatment with a rationally designed, cell permeant phosphopeptide mimetic of a downstream effector
protein of the NO pathway will bypass downregulated signaling elements, restore vasorelaxation, and
prevent delayed vasospasm after SAH. This approach is more targeted and stoichiometric than
approaches that activate or inhibit receptors or enzymes. In addition, this approach is particularly
useful in SAH where preventing systemic hypotension and optimizing cerebral vasodilation is
paramount.A family of cell permeant phosphopeptide analogues of a substrate of cGMP-dependent Protein
Kinase (PKG), and an actin-associated protein that modulates VSM relaxation, were rationally designed
and synthesized. Three candidate peptides were demonstrated to directly relax intact VSM in ex vivo
bioactivity assays. The peptide with the shortest sequence (denoted as VP3) and strongest bioactivity
was chosen as the optimal peptide for use to determine in vivo efficacy.Rupture of intracranial aneurysms leads to subarachnoid hemorrhage which is associated with
delayed vasospasm, leading to neuroischemic events (stroke) and neurobehavioral deficits, and
current therapeutic options are limited and only minimally effective. This project will determine
the efficacy of cell permeant therapeutic molecules in preventing delayed vasospasm and
improving functional outcomes after SAH in a rat model. These studies will identify and de-risk
a lead candidate molecule to advance for further pre-clinical studies to offer novel translatable
therapeutic approaches to prevent debilitating clinical sequelae of SAH-induced vasospasm.

* Information listed above is at the time of submission. *

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