Therapeutic methods that target the NCCA-ATP channel
Inventors
Simard, J. Marc • Chen, Mingkui
Assignees
US OF AMERICA A REPRESENTED BY Department OF VETERANS AFFAIRS • US Department of Veterans Affairs
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Publication Number
US-10583094-B2
Publication Date
2020-03-10
Expiration Date
2025-07-25
Abstract
The present invention is directed to therapeutic compositions targeting the NCCa-ATP channel of an astrocyte, neuron or capillary endothelial cell and methods of using same. More specifically, agonists and antagonists of the NCCa-ATP channel 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.
Core Innovation
The invention provides therapeutic compositions and methods that target a unique non-selective cation channel activated by intracellular calcium and blocked by intracellular ATP, called the NCCa-ATP channel, expressed in neuronal cells, neuroglial cells (such as astrocytes), or neural endothelial cells, particularly following brain insult such as ischemia, trauma, or cancer. The modulation of this channel by agonists or antagonists is used therapeutically to treat various diseases including cancer and cerebral edema.
The problem addressed is the presence of the NCCa-ATP channel in reactive astrocytes forming a gliotic capsule around brain injuries, tumors, or abscesses, where its opening leads to necrotic cell death and edema, contributing to brain swelling and impeding effective treatment. Additionally, metastatic brain tumors are protected by a tumor-brain barrier formed by reactive astrocytes expressing this channel, hindering immunologic surveillance and anti-cancer therapy. The invention solves these issues by providing methods to modulate the NCCa-ATP channel to either induce death of pathological cells (using agonists) to disrupt the tumor barrier or to prevent cell death and cerebral edema (using antagonists).
The invention comprehensively characterizes the NCCa-ATP channel as regulated by the sulfonylurea receptor 1 (SUR1), distinct from known KATP channels due to its non-selective cation permeability and calcium and ATP sensitivity. It provides methods of treating hyperproliferative diseases such as metastatic brain tumors using channel activators (agonists) to induce cytotoxic edema and cell death of tumor-associated astrocytes, thus disrupting the tumor-brain barrier and improving access of conventional therapies. Conversely, it uses channel inhibitors (antagonists) to prevent cell depolarization, reduce cytotoxic edema and cell death in ischemic conditions, for example cerebral ischemia or stroke.
Claims Coverage
The independent claims cover methods of treating acute cerebral ischemia and reducing stroke-related damage using compounds that inhibit the NCCa-ATP channel, administered with tissue plasminogen activator (tPA).
Use of NCCa-ATP channel inhibitors with tPA to increase therapeutic window and reduce stroke damage
A method of treating acute cerebral ischemia by administering effective amounts of tPA and a compound that inhibits the NCCa-ATP channel, whereby the inhibitor increases the therapeutic window for tPA, reduces hemorrhagic conversion, cell swelling, or edema, or both.
Expression of NCCa-ATP channel on specific neural cell types
The NCCa-ATP channel is expressed on neuronal cells, neuroglia cells, neural endothelial cells, or combinations thereof, which are targeted by the treatment.
Selection of specific sulfonylurea compounds as NCCa-ATP channel inhibitors
The compound inhibiting the NCCa-ATP channel is selected from sulfonylurea compounds including glibenclamide, tolbutamide, repaglinide, nateglinide, meglitinide, glyclazide, glimepiride, and related compounds.
Specified dosing ranges and administration routes for the inhibitors
The methods define dosing ranges for the compounds administered (e.g., 0.0001 μg/kg/day to 20 mg/kg/day) and modes of administration, including bolus injections, infusions, or combinations thereof, via alimentary, parenteral, topical, mucosal, or direct brain injection routes.
Inhibition mechanism reduces Na+ influx to prevent cell depolarization and cytotoxic edema
The administered compound inhibits sodium ion influx into cells, thus preventing or reducing cell depolarization and cytotoxic edema, thereby reducing hemorrhagic conversion and cell death in neuronal and endothelial cells during stroke.
Flexibility in timing of compound administration relative to tPA treatment
The inhibitor compound can be administered before, after, or simultaneously with tPA administration, providing flexible treatment protocols.
The independent claims primarily cover therapeutic methods of administering sulfonylurea or related compounds that inhibit the NCCa-ATP channel in combination with tPA to enhance stroke treatment by increasing therapeutic window, reducing hemorrhagic conversion, edema, and cell death, with detailed specification of compounds, dosages, cell targets, and administration routes.
Stated Advantages
Increased therapeutic window for thrombolytic agents such as tPA when used with NCCa-ATP channel antagonists.
Reduction of hemorrhagic conversion and cerebral edema in ischemic stroke treatment.
Selective disruption of tumor-brain barrier allowing improved access of anti-cancer therapies to metastatic brain tumors.
Neuroprotection by reducing necrotic cell death and cytotoxic edema in ischemic and traumatic brain injury.
Facilitation of diagnosis and monitoring of stroke and tumor boundaries using labeled NCCa-ATP channel antagonists.
Documented Applications
Treatment of metastatic brain tumors by administering agonists of the NCCa-ATP channel to disrupt the tumor-brain barrier and induce necrotic cell death of astrocytes.
Treatment of cerebral ischemia or stroke by administering antagonists of the NCCa-ATP channel to inhibit cell depolarization and reduce cytotoxic edema and hemorrhagic conversion.
Combination therapy with NCCa-ATP channel antagonists and thrombolytic agents such as tissue plasminogen activator (tPA) to increase the therapeutic window and reduce stroke-related damage.
Methods for diagnosing neuronal cell edema or cytotoxic damage in the brain using labeled antagonists of SUR1, including tumor boundary definition and stroke penumbra visualization.
Use of therapeutic kits comprising NCCa-ATP channel modulators with other pharmacological agents (anticoagulants, vasodilators, diuretics, statins) for neuroprotection and stroke treatment.
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