Methods for treating inflammatory disorders and traumatic brain injury using stabilized non-hematopoietic EPO short peptides
Inventors
Wang, Bo • Yuan, Rui R. • Lu, Wei • Dowling, Peter
Assignees
US Department of Veterans Affairs
Publication Number
US-10010583-B2
Publication Date
2018-07-03
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 described invention provides methods for treating inflammatory brain diseases, disorders or conditions and for treating traumatic brain injury having an inflammatory component using isolated erythropoietin (EPO)-derived oligopeptides. These EPO-derived oligopeptides include cyclic peptides such as JM-4, JM-5, and JM-7, which can be stabilized by adding small bicyclic compounds like biotin. The invention enables utilizing the neuroprotective capabilities of EPO without eliciting hematopoietic side effects such as increased red blood cell mass.
Traumatic brain injury (TBI) causes acute and secondary brain damage including inflammation, brain swelling, neuronal and glial cell death, and neurological deficits, with no effective pharmacological treatments for preventing secondary injury. Treatments using whole molecule EPO are limited by the risk of overstimulating erythropoiesis leading to elevated hematocrit and associated morbidity. The invention addresses this problem by using stabilized, isolated short EPO-derived peptides that maintain neuroprotective and immunomodulatory effects while preserving normal red blood cell indices during treatment.
Claims Coverage
The patent claims comprise two independent method claims focused on treating inflammatory brain diseases and traumatic brain injury using isolated EPO-derived oligopeptides with specified sequences.
Use of specific isolated erythropoietin-derived oligopeptides for treatment
The method involves administering a pharmaceutical composition comprising a therapeutically effective amount of at least one isolated erythropoietin-derived oligopeptide selected from SEQ ID NO: 1 (JM-4), SEQ ID NO: 5, SEQ ID NO: 9 (JM-5), SEQ ID NO: 18, SEQ ID NO: 27, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 35, and SEQ ID NO: 37, together with a pharmaceutically acceptable carrier, effective in treating an inflammatory brain disease or traumatic brain injury.
Cyclic peptide form of EPO-derived oligopeptides
The isolated erythropoietin-derived oligopeptide used in treatment is a cyclic peptide.
Stabilized oligopeptides with small bicyclic compounds
The isolated erythropoietin-derived oligopeptide can be a stabilized form comprising at least one small bicyclic compound attached at the N-terminal or C-terminal end of the oligopeptide.
Treatment of specific inflammatory brain diseases
The method is applicable to inflammatory brain diseases including multiple sclerosis, demyelinating diseases, chronic inflammatory brain diseases, and complications following traumatic brain injury.
Timing of administration after traumatic brain injury
The administration of the pharmaceutical composition may occur within windows ranging from about 15 minutes to about 24 hours following the traumatic brain injury.
Reduction of mononuclear cell infiltration
The method may further include reducing infiltration of mononuclear cell populations into the brain of the subject during treatment.
Maintenance of hematocrit levels
The method includes maintaining red blood cell indices such as hematocrit at stable levels or within about 20% of a baseline or reference value during treatment.
The independent claims focus on methods for treating inflammatory brain diseases and traumatic brain injury using specific isolated EPO-derived oligopeptides, including cyclic and stabilized forms, with defined sequences, effectively reducing inflammatory symptoms and cellular damage while maintaining normal hematological parameters. The claims include timing of administration and immunomodulatory effects such as reducing mononuclear cell infiltration.
Stated Advantages
The peptides exhibit neuroprotective capabilities similar to whole molecule EPO but without hematopoietic side effects such as increased red blood cell mass or elevated hematocrit.
Treatment with short EPO-derived peptides leads to marked clinical improvement in neurologic deficits in animal models of inflammatory brain disease and traumatic brain injury.
The peptides reduce neuroinflammation by decreasing mononuclear cell infiltration into the brain and protecting against axonal damage and neuronal and glial cell death.
The addition of small bicyclic compounds such as biotin stabilizes the peptides, increasing their stability without reducing biological activity.
The peptides maintain red blood cell indices at substantially normal levels during treatment, avoiding risks associated with whole EPO therapy.
Documented Applications
Treatment of traumatic brain injury, including symptoms such as hypotension, hypoxemia, brain swelling, headache, neck pain, cognitive difficulties, fatigue, mood changes, seizures, coma, muscle weakness, paralysis, and progressive neurological decline.
Treatment of inflammatory brain diseases such as multiple sclerosis, demyelinating diseases, and chronic neurodegenerative inflammatory brain diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and age-related macular degeneration.
Treatment of complications following traumatic brain injury.
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