UG3NS125023

Strategy for Improving Stroke Treatment Response (SISTER) Trial - The Introduction of Recombinant Tissue Plasminogen Activators (R-TPA, Alteplase) 25 years ago, and the recent development of endovascular therapy (EVT), significantly reduced neurologic disability in patients with ischemic stroke. Still, only 20% of stroke patients in the US are eligible for these therapies and 70% of those treated are left disabled. Unfortunately, these therapies are also associated with toxic effects such as brain hemorrhage.

For many patients, such as those who would be treated at 4.5-24 hours after stroke without large vessel occlusion, no established therapy exists. We urgently need to develop safer and more effective treatments that can lessen the suffering and enormous costs of disability after ischemic stroke.

NINDS-funded research shows that A2-antiplasmin (A2AP) is a molecule that plays a crucial, deleterious role in acute ischemic stroke. High A2AP levels are linked to an increased risk of R-TPA failure clinically, and A2AP increases brain injury in a dose-dependent fashion in preclinical models. A2AP blocks thrombus dissolution initiated by R-TPA and increases microvascular thrombosis. A2AP promotes neutrophil recruitment and matrix metalloproteinase-9 (MMP-9) expression, which enhances blood-brain barrier breakdown to cause intracranial hemorrhage.

Conversely, A2AP deficiency, or a monoclonal antibody that inactivates A2AP (A2AP-I), profoundly reduces apoptosis, MMP-9 expression, microvascular thrombosis, hemorrhage, and swelling by comparison to R-TPA or no treatment. Importantly, an A2AP-I has a several-fold longer therapeutic window than R-TPA. Compared to R-TPA, an A2AP-I significantly decreases brain infarction, brain hemorrhage, disability, and mortality in preclinical stroke. Robust studies from multiple labs, using different models and tools, show consistent effects. Taken together, these data suggest that an A2AP-I alone has extraordinary potential for safe treatment of human ischemic stroke, particularly in an extended ischemic time window.

The monoclonal antibody A2AP-I, TS23, was developed with NIH/NINDS research support. In a Phase I trial of healthy volunteers, TS23 induced dose-related A2AP inactivation, amplified endogenous thrombus dissolution, and was well-tolerated. A randomized, placebo-controlled, blinded, Bayesian, dose-finding, Phase II SISTER trial within the NIH StrokeNet will test the central hypothesis that, when compared to standard medical care, TS23 will safely improve neurological outcomes in patients with extended ischemia, without completed infarction.

TS23 will be compared to placebo in 300 acute ischemic stroke patients presenting 4.5-24 hours after symptom onset with favorable perfusion imaging. If TS23 proves to be safe and potentially efficacious, based on reduction of neurological impairment, a future, pivotal clinical trial will be planned.

Cincinnati Univ Of

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Ohio United States

State-Wide

NIH StrokeNet Clinical Trials and Biomarker Studies for Stroke Treatment, Recovery, and Prevention (UG3/UH3 Clinical Trial Optional) (PAR-20-285)

Amendment Since initial award the End Date has been shortened from 06/30/28 to 06/30/24 and the total obligations have decreased 34% from $5,110,320 to $3,394,490.