Compositions and methods for modulating neuronal excitability and motor behavior
Inventors
Schaefer, Anne • Greengard, Paul • Tan, Chan Lek
Assignees
Rockefeller University • Icahn School of Medicine at Mount Sinai
Publication Number
US-12163130-B2
Publication Date
2024-12-10
Expiration Date
2034-10-28
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Abstract
The invention is directed to compositions and methods for treating or reducing the likelihood of the development of epilepsy in an individual. The method comprises administering to the central nervous system of an individual in need of such treatment a therapeutically effective amount of an agent capable of increasing the expression and/or activity of miR-128.
Core Innovation
The invention relates to compositions and methods for treating or reducing the likelihood of the development of epilepsy and related seizure disorders by increasing the expression and/or activity of microRNA-128 (miR-128) in the central nervous system. Specifically, the administration of a therapeutically effective amount of an agent that enhances miR-128 activity or expression to an individual in need is disclosed as a therapeutic strategy to control neuronal excitability and motor activity, thereby preventing or mitigating seizures and epilepsy.
The problem addressed is the lack of effective treatments for epilepsy, especially for about one-third of patients who do not respond to existing medications. Epilepsy is characterized by recurrent seizures caused by abnormal and excessive neuronal discharges. Current pharmacological treatments fail to prevent or cure epilepsy and often only inhibit seizures in a subset of patients. There is a significant unmet need for alternative therapeutic approaches that can prevent the development of seizures, particularly in individuals at risk due to brain injuries such as stroke or trauma.
The inventors discovered that miR-128 is highly expressed in the adult brain and plays a critical role in modulating neuronal excitability by regulating ion channels and signaling pathways, including the ERK2 network. Deficiency of miR-128 in neurons leads to hyperactivity and fatal epilepsy in mice, whereas overexpression attenuates neuronal responsiveness and prevents seizures. The invention thus proposes therapeutics based on miR-128 or agents increasing its expression/activity for treating epilepsy, status epilepticus, and related neurologic injuries, including in patients diagnosed with Dravet Syndrome and those suffering from brain injuries that increase epilepsy risk.
Claims Coverage
The patent includes three independent claims directed to methods of treating or reducing the likelihood of epilepsy or temporal lobe epilepsy by administering agents related to miR-128 to individuals at risk due to brain injury.
Use of agents comprising the seed region of miR-128 for treatment
Administering to an individual who has suffered traumatic brain injury or stroke an agent comprising the seed region of microRNA-128 (nucleotides 2 through 7 of SEQ ID NO: 1) or a polynucleotide encoding a transcript with this seed region to treat or reduce temporal lobe epilepsy or epilepsy risk.
Routes and targets of administration
Administering the agent intrathecally or intranasally, or to the central nervous system including specific brain regions such as the hippocampus and/or cortex.
Chemical stabilization and sequence homology of agents
Using agents that are chemically stabilized polynucleotides or have 90 percent or more sequence identity to miR-128 (SEQ ID NO: 1) to enhance therapeutic efficacy and stability.
Use of viral vectors for agent delivery
Employing viral vectors encoding miR-128 or its relevant seed region to achieve expression in the target brain tissue for treating or reducing the likelihood of epilepsy development.
The claims cover methods of treating or preventing epilepsy in individuals at risk due to brain injury by administering agents that increase miR-128 activity or expression, focusing on specific nucleic acid sequences corresponding to the seed region of miR-128, delivery routes, chemical modifications, and vector-based expression systems to achieve therapeutic benefit.
Stated Advantages
Provides a novel therapeutic strategy for treating or preventing epilepsy by targeting a microRNA that modulates neuronal excitability.
Effective in reducing seizure susceptibility, including in pharmacoresistant epilepsy such as Dravet Syndrome.
Targets multiple genes within neuronal signaling networks, offering broad control over excitability and motor behavior.
Can be administered via central nervous system targeted routes such as intrathecal or intranasal delivery.
Documented Applications
Treatment or prevention of epilepsy and status epilepticus in individuals at risk, including those with brain injuries caused by stroke or trauma.
Suppression or reduction of spontaneous recurrent seizures in individuals with brain-related disorders characterized by seizures, e.g., stroke, hypoxia, traumatic brain injury, infection, tumor, neurodegenerative disorders, metabolic and autoimmune diseases.
Treatment of patients diagnosed with Dravet Syndrome and other severe seizure disorders.
Use of miR-128 agents in pharmaceutical compositions for reducing neuronal pathologies characterized by seizures.
Identification of compounds that increase miR-128 activity useful in seizure-related pathologies through cell-based assays.
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