Methods for treating inflammatory disorders and traumatic brain injury using stabilized non-hematopoietic EPO short peptides
Inventors
Wang, Bo • Yuan, Rui Rong • Lu, Wei • Dowling, Peter C.
Assignees
US Department of Veterans Affairs
Publication Number
US-9345745-B2
Publication Date
2016-05-24
Expiration Date
2026-05-01
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Abstract
The described invention provides methods for treating an inflammatory brain disease, disorder or condition and for treating a traumatic brain injury having an inflammatory component in a subject in need thereof using isolated erythropoietin (EPO)-derived oligopeptides.
Core Innovation
The invention provides methods for treating an inflammatory brain disease, disorder or condition as well as traumatic brain injury (TBI) having an inflammatory component in a subject using isolated erythropoietin (EPO)-derived oligopeptides. The methods involve administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of at least one isolated EPO-derived oligopeptide and a pharmaceutically acceptable carrier, treating at least one symptom of the brain disease or injury, and maintaining red blood cell indices at substantially normal levels during treatment.
The problem being solved addresses the debilitating effects of TBI, including secondary brain injury caused by inflammation-induced brain swelling, increased intracranial pressure, and neuronal cell death, which contribute to long-term disability and poor outcomes. Previous treatments, including various pharmacological agents, have not proven effective in preventing secondary injury following TBI. Moreover, while whole molecule EPO has neuroprotective properties, its use is limited due to harmful hematopoietic side effects, such as excessive erythropoiesis and elevated hematocrit, which can increase morbidity and mortality.
The invention solves these issues by providing stabilized short EPO-derived peptides, such as cyclic peptides JM-4, JM-5, and JM-7, which retain the neuroprotective and anti-inflammatory capabilities of full-length EPO without provoking hematopoietic side effects. The peptides modulate immune-mediated inflammatory networks by reducing mononuclear cell infiltration, axonal damage, neuronal and glial cell death, and improving neurological deficits after inflammatory brain disease or traumatic brain injury. The peptides may be further stabilized by conjugation with small bicyclic compounds like biotin, enhancing their stability without compromising biological activity.
Claims Coverage
The patent includes one independent claim defining a method of treating an inflammatory brain disease or traumatic brain injury using a specific EPO-derived peptide and a pharmaceutically acceptable carrier. It focuses on administration timing, peptide stabilization, and therapeutic effects while maintaining normal red blood cell indices.
Use of a specific EPO-derived oligopeptide JM-4 in treatment
The method involves providing a pharmaceutical composition comprising a therapeutically effective amount of an erythropoietin (EPO)-derived oligopeptide of JM-4 (SEQ ID NO:1) and a pharmaceutically acceptable carrier.
Administration of the pharmaceutical composition to a subject in need
Administering the pharmaceutical composition comprising JM-4 peptide to treat an inflammatory brain disease or traumatic brain injury in a subject.
Use of cyclic peptide structure
The EPO-derived oligopeptide used in the method is a cyclic peptide, enhancing stability and biological activity.
Stabilization of the oligopeptide by bicyclic compound addition
The method uses a stabilized isolated erythropoietin-derived oligopeptide which includes at least one small bicyclic compound, such as biotin, added to either the N-terminal or C-terminal ends of the oligopeptide.
Timely administration following traumatic brain injury
The method includes administering the pharmaceutical composition within a timeframe after traumatic brain injury, specifically within about 15 minutes, 1 hour, 3 hours, 6 hours, 9 hours, or up to about 24 hours post-injury.
Reducing inflammatory and neural damage
The method further comprises reducing infiltration of mononuclear cells into the brain and reducing axonal damage in brain regions affected by the traumatic brain injury.
Maintaining hematocrit at stable levels
The method comprises maintaining the subject's hematocrit at a stable level or within about 20% of a reference or baseline value during treatment.
The claims cover methods of treating inflammatory brain diseases and traumatic brain injuries using JM-4 EPO-derived cyclic peptides, optionally stabilized with bicyclic compounds, administered within a therapeutic time window post-injury. The methods alleviate brain inflammation and neural damage while maintaining stable hematocrit levels, thus avoiding hematopoietic side effects typically associated with whole molecule EPO.
Stated Advantages
The methods provide neuroprotection without increasing red blood cell mass or hematocrit, avoiding detrimental hematopoietic side effects seen with whole molecule EPO.
The short EPO-derived peptides reduce neurological deficits, neuronal and glial cell death, axonal injury, and mononuclear cell infiltration in the brain.
The peptides exhibit neuroprotective and immunomodulatory effects in various brain inflammatory disorders, including traumatic brain injury and multiple sclerosis models.
Stabilization of peptides with small bicyclic compounds, such as biotin, enhances peptide stability without compromising biological activity.
The therapeutic window for peptide administration extends up to at least 9 hours post-traumatic brain injury, facilitating clinical applicability.
Documented Applications
Treatment of inflammatory brain diseases, including multiple sclerosis and chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and age-related macular degeneration.
Treatment of traumatic brain injury (TBI), including both open and closed head injuries, and their inflammatory complications.
Reduction of neurological symptoms and deficits resulting from traumatic brain injury, including hypotension, hypoxemia, brain swelling, headache, neck pain, cognitive difficulties, fatigue, mood changes, nausea, vision and sensory losses, seizures, coma, muscular weakness, paralysis, and progressive neurological decline.
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