Lee J.H.,Emory University |
Wei L.,Emory University |
Gu X.,Emory University |
Wei Z.,Emory University |
And 3 more authors.
Journal of Neurotrauma | Year: 2014
Preclinical and clinical studies have shown therapeutic potential of mild-to-moderate hypothermia for treatments of stroke and traumatic brain injury (TBI). Physical cooling in humans, however, is usually slow, cumbersome, and necessitates sedation that prevents early application in clinical settings and causes several side effects. Our recent study showed that pharmacologically induced hypothermia (PIH) using a novel neurotensin receptor 1 (NTR1) agonist, HPI-201 (also known as ABS-201), is efficient and effective in inducing therapeutic hypothermia and protecting the brain from ischemic and hemorrhagic stroke in mice. The present investigation tested another second-generation NTR1 agonist, HPI-363, for its hypothermic and protective effect against TBI. Adult male mice were subjected to controlled cortical impact (CCI) (velocity=3 m/sec, depth=1.0 mm, contact time=150 msec) to the exposed cortex. Intraperitoneal administration of HPI-363 (0.3 mg/kg) reduced body temperature by 3-5°C within 30-60 min without triggering a shivering defensive reaction. An additional two injections sustained the hypothermic effect in conscious mice for up to 6 h. This PIH treatment was initiated 15, 60, or 120 min after the onset of TBI, and significantly reduced the contusion volume measured 3 days after TBI. HPI-363 attenuated caspase-3 activation, Bax expression, and TUNEL-positive cells in the pericontusion region. In blood-brain barrier assessments, HPI-363 ameliorated extravasation of Evans blue dye and immunoglobulin G, attenuated the MMP-9 expression, and decreased the number of microglia cells in the post-TBI brain. HPI-363 decreased the mRNA expression of tumor necrosis factor-α and interleukin-1β (IL-1β), but increased IL-6 and IL-10 levels. Compared with TBI control mice, HPI-363 treatments improved sensorimotor functional recovery after TBI. These findings suggest that the second generation NTR-1 agonists, such as HPI-363, are efficient hypothermic-inducing compounds that have a strong potential in the management of TBI. © 2014, Mary Ann Liebert, Inc.
Ghatnekar G.S.,FirstString Research, Inc. |
Ghatnekar G.S.,Halimed Pharmaceuticals, Inc. |
Ghatnekar G.S.,Regranion LLC |
Elstrom T.A.,FirstString Research, Inc. |
Elstrom T.A.,Regranion LLC
Methods in Molecular Biology | Year: 2013
This chapter will outline strategies and ideas for the commercialization a promising wound healing technology discovered in an academic setting. This would include, but not limited to addressing topics such as intellectual property protection, funding, technology development, and regulatory aspects (i.e., navigating through the FDA). © 2013 Springer Science+Business Media New York.
Choi K.-E.,Emory University |
Hall C.L.,Emory University |
Sun J.-M.,Emory University |
Wei L.,Emory University |
And 5 more authors.
FASEB Journal | Year: 2012
Compelling evidence from preclinical and clinical studies has shown that mild to moderate hypothermia is neuroprotective against ischemic stroke. Clinical applications of hypothermia therapy, however, have been hindered by current methods of physical cooling, which is generally inefficient and impractical in clinical situations. In this report, we demonstrate the potential of pharmacologically induced hypothermia (PIH) by the novel neurotensin receptor 1 (NTR1) agonist ABS-201 in a focal ischemic model of adult mice. ABS-201 (1.5-2.5 mg/kg, i.p.) reduces body and brain temperature by 2-5° C in 15-30 min in a dose-dependent manner without causing shivering or altering physiological parameters. Infarct volumes at 24 h after stroke are reduced by ~30-40% when PIH therapy is initiated either immediately after stroke induction or after 30-60 min delay. ABS-201 treatment increases bcl-2 expression, decreases caspase-3 activation, and TUNEL-positive cells in the peri-infarct region, and suppresses autophagic cell death compared to stroke controls. The PIH therapy using ABS-201 improves recovery of sensorimotor function as tested 21 d after stroke. These results suggest that PIH induced by neurotensin analogs represented by ABS-201 are promising candidates for treatment of ischemic stroke and possibly for other ischemic or traumatic injuries. © FASEB.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 3.00M | Year: 2005
DESCRIPTION (provided by applicant): This is the follow-on Phase II SBIR proposal to continue the project Novel Neurotensin Analogs as Antischizophrenics (MH-65099) under PA-06-079 (Pharmacological Agents and Drugs for Mental Disorders). There exists a critical clinical need for the identification and development of novel therapies for psychosis, a major unmet medical need. Low levels of the brain peptide neurotensin (NT) have been linked to schizophrenia, hence NT receptor agonists that can be delivered to the brain have significant potential for development as a new class of antipsychotics that might not have the side- effects associated with current drugs. In Phase I and the first year of Phase II of this program, ABS201, a derivative of the active fragment of NT, NT[8-13], was identified as the most promising lead for development from a comprehensive screen of over 50 NT[8-13] analogs. This compound showed strong efficacy in the key rat models of psychosis, did not cause catalepsy, and animals did not develop resistance to it. Most notably, it is active at a druggable dose when administered orally. During the rest of the Phase II proposal, a detailed preclinical and clinical plan was completed for further development of ABS201, and many of the IND-enabling experiments were completed with successful outcomes. In addition, a critical set of experiments to define the site and mechanism of action of the compound was completed successfully. The goal of this follow-on Phase II is to perform activities necessary for advancing ABS201 through Phase I of clinical trials. This will be achieved through completion of four Specific Aims. In Specific Aim 1, GMP synthesis of sufficient amounts of the compound to finish preclinicals and bridge it into the Phase I clinical trial will be performed. In Specific Aim 2 the outstanding preclinical experiments will be completed enabling preparation and submission of the IND, the goal of Specific Aim 3. Completion of the Phase I clinical trial is the objective of Specific Aim 4. Specific Aim 1 will be completed at Genzyme Pharmaceuticals, the designated GMP synthesis laboratory. Specific Aim 2 will be managed by Argolyn in collaboration with Summit Drug Development (who wrote the clinical plan) using high quality CROs to perform the experiments. Specific Aims 3 and 4 will be managed by Argolyn and Summit with the site(s) of the Phase I trials to be determined. Evidence linking NT to schizophrenia has accumulated over the last 30 years, the proposed clinical trial would be the first in which a NT derivative is evaluated in humans. PUBLIC HEALTH RELEVANCE: During Phase I and II of this project a derivative of the endogenous brain peptide neurotensin, ABS-201, has demonstrated the characteristics necessary for development as an orally available, first-in-class antipsychotic. Completion of various activities designed to take ABS201 through Phase I of clinical trials, including synthesis of GMP-grade material, completion of preclinicals, and the preparation and submission of an IND, is the goal of this proposal.
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 883.73K | Year: 2011
DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the United States. In spite of intensive investigations, clinical therapies for treating acute stroke patients remain limited and unsatisfactory. There are consistent animal and human data that mild to moderate hypothermia (reducing body temperature to 32-34oC) is generally safe and improves outcome after brain ischemia even when initiated hours after ischemia occurs. Different from most neuroprotective drugs that usuallytarget only one mechanism, hypothermia therapy has the advantage of global protection on all cell types and tissues in both gray and white matters. Several important limitations, however, have precluded the widespread use of hypothermia therapy in strokepatients. The major obstruction is that existing forced cooling techniques are ineffectual and/or impractical in clinical settings. To overcome the shortcomings of current methods, the concept of regulated hypothermia induced by pharmacological means has been proposed as a new strategy in hypothermia therapy; although there have been no drugs that can be used for regulated hypothermia therapy. To this end, we have synthesized and tested novel neurotensin(NT)[8-13] derivatives, such as ABS201 and ABS601,that are potent hypothermic compounds and have dramatic neuroprotective activity in animal stroke models. These NT compounds show no toxic effects, attenuate infarct formation by nearly 50% even when administered 45 min after the onset of ischemia. The mechanism of protection appears to involve their ability to cross the blood brain barrier, bind to the NT receptor as agonists, and reduce the set point of the central temperature control so that systemic hypothermia in the absence of shivering is promoted. It is thus hypothesized that NT/ABS derivatives have strong potential of being developed for regulated hypothermia therapy. In the Phase I study, we will compare the hypothermic potency of six NT/ABS derivatives. Two leading compounds without detectableside effects will be tested and compared for their neuroprotection in aged rats of two stroke models of transient and permanent ischemia. This translational investigation is not intended to delineate the mechanism of hypothermia protection, which has beenextensively studied so far. Rather, we aim to demonstrate the feasibility of the chemical-induced hypothermia therapy and move to more systematic preclinical examinations of a Phase II investigation. Our ultimate goal is to advance the drug-induced hypothermia therapy to the clinic. PUBLIC HEALTH RELEVANCE: Ischemic stroke is the third leading cause of human death and disability in the US. This investigation will develop a chemical-induced hypothermia therapy for stroke patients. The comprehensive neuroprotective effects of clinically feasible hypothermia therapy will be studied in two different stroke models, which will facilitate the translation of the therapy to clinical applications.