We shall develop a safe, effective therapy against zinc neurotoxicity, a major cause of neuronal injury in man. Zinc-induced neuronal injury is emerging as a core component of the excitotoxic cascade occurring after stroke, ischemia, seizures, and blunt trauma. Moreover, we have new evidence that Zn2+ promotes formation of both amyloid plaques and neurofibrillary tangles in Alzheimer's disease. We and others have already shown that zinc chelation can reduce and/or reverse this neuronal injury in several animal models. For therapeutic drug design, we will capitalize on our proprietary, """"""""custom-made"""""""" (point-mutated) zinc-binding proteins. Transport of these zinc-binding proteins into the brain will utilize antibodies against transcytotic carriers (e.g., OX-26) that can carry proteins through the blood-brain barrier. This approach will allow design of therapeutic CNS """"""""zinc buffers"""""""" that maintain safe, appropriate, physiological levels of extracellular Zn2+ without perturbing intracellular zinc. In Phase I, we will (i) screen candidate point-mutated proteins for zinc- binding properties and neuroprotective potency, (ii) develop attachment chemistry for linking to transport antibodies, and (iii) test promising leads in rodent models of both Alzheimer-like and excitotoxic models of zinc toxicity. In Phase II, in vivo animal testing will continue with FDA preclinical trials targeted for Phase II-Phase III.

Proposed Commercial Applications

Head/brain injury is the leading cause of death among individuals under 50. Stroke, CVA, and seizures strike many more victims, and cerebral ischemia due to cardiac failure or surgical procedures befall yet another group. An effective neruoprotective drug that could reduce the excitotoxic/ischemic injury to brain cells in all of these conditions would have a frankly enormous market. Further, a drug for regulating cerebral Zn2+, if that indeed slows the advance of Alzheimer's pathology, would find yet a second market.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-BDCN-1 (02))
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Kitt, Cheryl A
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Neurobiotex, Inc.
United States
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