Methods of neuroprotection involving macrophage colony stimulating factor receptor agonists
Inventors
Assignees
US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-9770486-B2
Publication Date
2017-09-26
Expiration Date
2032-04-07
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Abstract
Disclosed are novel methods for preventing or attenuating neuronal damage or stimulating neuronal repair, prior to or following central nervous system injury associated with acute or chronic nervous system injury. Macrophage colony stimulating factor receptor agonists including macrophage colony stimulating factor (M-CSF or CSF-1), interleukin-34 (IL-34), proteins or biologically active fragments thereof, peptides or biologically active fragments thereof, peptidomimetics, or small molecules, and the like are effective for prevention or treatment of acute nervous system injury or chronic nervous system injury involving Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and the like.
Core Innovation
The invention provides novel methods for preventing or attenuating neuronal damage and stimulating neuronal repair following acute or chronic injury of nerve cells of the central nervous system. These methods involve the administration of macrophage colony stimulating factor receptor agonists locally at or near a site of injury or systemically in a therapeutically effective amount and within a time period sufficient to produce a therapeutic effect. The macrophage colony stimulating factor receptor agonists include macrophage colony stimulating factor (M-CSF or CSF-1), interleukin-34 (IL-34), proteins or biologically active fragments thereof, peptides or biologically active fragments thereof, peptidomimetics, or small molecules.
The methods also encompass the prevention or attenuation of neuronal damage prior to an acute or chronic injury of nerve cells of the central nervous system through administration of such agonists. A therapeutically effective amount and timing prior to injury are defined as sufficient to provide a therapeutic effect. The invention demonstrates that these agonists can exert neuroprotective effects both when administered before and after a neuronal insult.
The problem addressed involves permanent neurological damage caused by traumatic brain injury, cerebral ischemia, metabolic insults such as glucose deprivation and oxidative stress, as well as neurodegenerative disorders. Existing neuroprotective factors have not translated into effective treatments following neuronal insults, hence current therapies do not adequately stop neuronal cell loss and death. Therefore, there is a need for new therapeutic agents available for immediate or preemptive treatment to mitigate or prevent neuronal cell death.
Claims Coverage
The patent contains 15 claims with multiple inventive features focused on methods of administering IL-34 or biologically active fragments thereof to human subjects for neuroprotection and neuronal repair.
Administration of IL-34 following acute central nervous system injury
A method of attenuating neuronal damage in a human subject following acute central nervous system injury by administering a pharmaceutical composition comprising at least one macrophage colony stimulating factor receptor agonist, specifically Interleukin-34 (IL-34) or a biologically active fragment thereof, within a predetermined time period following injury.
Treatment of acute central nervous system injuries
The acute central nervous system injury treated can be caused by traumatic brain injury, cerebral ischemia, cerebral glucose deprivation, cerebral oxidative stress, spinal cord injury, or excitotoxic injury.
Use of IL-34 or its biologically active fragments as agonists
The macrophage colony stimulating factor receptor agonist used in the methods may comprise IL-34 or biologically active fragments of IL-34.
Stimulation of neuronal repair post acute CNS injury
A method to stimulate neuronal repair in humans following acute CNS injury via administration of a pharmaceutical composition comprising IL-34 or a biologically active fragment thereof within a predetermined time following injury.
Treatment of Alzheimer's disease with IL-34
A method to stimulate neuronal repair or attenuate neuronal damage in a human subject suffering from Alzheimer's disease through administration of IL-34 or its biologically active fragments during the course of the disease.
Pre-onset treatment of Alzheimer's disease risk
A method to attenuate neuronal damage in humans at risk of Alzheimer's disease prior to onset by administering IL-34 or a biologically active fragment thereof.
The claims collectively focus on therapeutic methods involving administering IL-34 or its biologically active fragments as macrophage colony stimulating factor receptor agonists to human subjects for attenuating neuronal damage and stimulating neuronal repair following various acute CNS injuries and Alzheimer's disease, both preemptively and during disease progression.
Stated Advantages
Macrophage colony stimulating factor receptor agonists such as M-CSF and IL-34 improve cognitive function in animal models of Alzheimer's disease.
These agonists attenuate neuronal damage and stimulate neuronal repair in various models of acute neurodegeneration.
The neuroprotective effects can be exerted both before and after neuronal injury, offering flexibility in clinical application.
Systemically administered agonists reduce excitotoxic neuronal injury and neuroinflammation without recruitment of peripheral inflammatory cells.
M-CSF and IL-34 activate CREB signaling pathways in neurons, mediating neuroprotection.
Agonist administration reduces glial activation and neurodegeneration following toxic insult.
Documented Applications
Treatment or prevention of neuronal damage and stimulation of neuronal repair following acute central nervous system injuries such as traumatic brain injury, cerebral ischemia, glucose deprivation, oxidative stress, spinal cord injury, and excitotoxic injury.
Treatment of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.
Improvement of cognitive function and reduction of neurodegeneration in transgenic mouse models of Alzheimer's disease.
Post-injury therapeutic use to reduce neuronal damage and neuroinflammation as demonstrated in kainic acid excitotoxicity mouse models.
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