University System of Maryland

The United States Government as Represented by the Department of Veterans Affairs

Biogen Chesapeake LLC

J Marc Simard

Mingkui Chen

Sven Jacobson

Vladimir Gerzanich

The present invention concerns protection of an organ or tissue outside of the central nervous system following an ischemic episode. In particular aspects, the invention concerns organ preservation for transplantation, angina pectoris, kidney reperfusion injury, and so forth. In specific embodiments, the organ is subjected to an inhibitor of an NCchannel that is regulated by SUR1. Exemplary inhibitors include sulfonylurea compounds, such as glibenclamide, for example.

Targeting NCchannel for organ protection following ischemic episode

Embodiments of the disclosure encompass methods and/or compositions for ameliorating or preventing intimal damage caused by mechanical stimulation of endothelial cells. The damage may be caused by use of a device within an artery, vein, or capillary of an individual, such as to remove a thrombus, an embolus or an atherosclerotic plaque in the vessel. Treatment and prevention embodiments concern therapeutically effective amounts of one or more antagonists of the SUR1-TRPM4 channel that is upregulated upon the mechanical stimulation.

Methods of reducing or preventing intimal damage caused by mechanical stimulation of endothelial cells

The present invention is directed to therapeutic compositions targeting the NCchannel of an astrocyte, neuron or capillary endothelial cell and methods of using same. More specifically, agonists and antagonists of the NCchannel are contemplated. The therapeutic compositions are used to treat cancer, more specifically, a metastatic brain tumor, wherein a tumor-brain barrier is present. Such treatments are contemplated in combination with conventional anti-cancer therapies. Alternatively, the compositions are used to prevent cell death and to treat cerebral edema that result from ischemia, due to interruption of blood flow, to tissue trauma or to increased tissue pressure.

Therapeutic methods that target the NCchannel

A composition comprising a novel Ca-activated, [ATP]-sensitive nonspecific cation (NC) channel is described. The channel is found in mammalian neural cells and exhibits a different sensitivity to block by various adenine nucleotides, and is activated by submicromolar [Ca]. The NCchannel is activated under conditions of ATP depletion, which causes severe cell depolarization, followed by cell swelling. The NCchannel is regulated by a sulfonylurea receptor and is inhibited by sulfonylurea compounds glibenclamide and tolbutamide. Methods employing compositions comprising the NCchannel to screen for compounds that block the channel and the use of such antagonists as therapeutics in preventing brain swelling and damage are described. In addition, methods employing compositions comprising the Kir2.3 channel to screen for compounds that open the channel and the use of such antagonists as therapeutics in preventing brain swelling and damage are described.

Methods for treating central or peripheral nervous system damage

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The present invention concerns protection of an organ or tissue following an ischemic episode In particular aspects, the invention concerns organ preservation for transplantation, angina pectoris, kidney reperfusion injury, and so forth In specific embodiments, the organ is subjected to an inhibitor of an NCCa-ATP channel that is regulated by SUR1 Exemplary inhibitors include sulfonylurea compounds, such as glibenclamide, for example.

Methods and compositions are provided that are utilized for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury. In particular, the methods and compositions are inhibitors of a particular NCca-ATP channel and include, for example, inhibitors of SURI and/or inhibitors of TRPM4. Kits for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury, are also provided. The present invention also concerns treatment and/or prevention of intraventricular hemorrhage in infants, including premature infants utilizing one or more inhibitors of the channel is provided to the infant, for example to brain cells of the infant.

Methods for treating neural cell swelling

The present invention is directed to therapeutic compounds, treatment methods, and kits affecting the NCchannel of neural tissue, including neurons, glia and blood vessels within the nervous system, and methods of using same. The NCchannel is newly expressed in neural tissue following injury such as ischemia, and is regulated by the sulfonylurea receptor SUR1, being inhibited by sulfonylurea compounds, e.g., glibenclamide and tolbutamide, and opened by diazoxide. Antagonists of the NCchannel, including SUR1 antagonists, are useful in the prevention, diminution, and treatment of injured or diseased neural tissue, including astrocytes, neurons and capillary endothelial cells, that is due to ischemia, tissue trauma, brain swelling and increased tissue pressure, or other forms of brain or spinal cord disease or injury. Agonists of the NCchannel may be are useful in the treatment neural tissue where damage or destruction of the tissue, such as a gliotic capsule, is desired.

Methods for treating brain swelling with a compound that blocks a non-selective cation channel

The present invention is directed to therapeutic compositions targeting the NCchannel of an astrocyte, neuron or capillary endothelial cell and methods of using same. More specifically, antagonists of the NCchannel are contemplated. The compositions are used to prevent cell death and to treat secondary damage associated with spinal cord injury.

Methods for treating spinal cord injury with a compound that inhibits a NCCA-ATP channel

Methods and compositions are provided that are utilized for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury. In particular, the methods and compositions are inhibitors of a particular NCca-ATP channel and include, for example, inhibitors of SUR1 and/or inhibitors of TRPM4. Kits for treatment and/or prevention of intraventricular hemorrhage or progressive hemorrhagic necrosis (PHN), particularly following spinal cord injury, are also provided. The present invention also concerns treatment and/or prevention of intraventricular hemorrhage in infants, including premature infants utilizing one or more inhibitors of the channel is provided to the infant, for example to brain cells of the infant.

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Baltimore, MD, United States of America

J Marc Simard