Erythropoietin-derived short peptide and its mimics as immuno/inflammatory modulators
Inventors
Yuan, Rui Rong • Li, Wei Ping • Maeda, Yasuhiro • Dowling, Peter C.
Assignees
US Department of Veterans Affairs
Publication Number
US-10047132-B2
Publication Date
2018-08-14
Expiration Date
2026-05-01
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Abstract
The present disclosure provides isolated stabilized EPO-derived peptides and their mimics that protect against tissue damage in subjects having diverse forms of neural and non-neural organ system injury, pharmaceutical compositions containing the isolated stabilized EPO-derived peptides, methods for treating symptoms of a disease, disorder or condition having an inflammatory or an autoimmune component in a subject in need thereof, and methods for downregulating immune mediator activity in a subject in need thereof.
Core Innovation
The invention provides isolated stabilized erythropoietin (EPO)-derived short peptides and their mimics that protect against tissue damage in subjects with diverse neural and non-neural organ system injury. These peptides possess non-hematopoietic biological activity and are stabilized to maintain efficacy during storage at 4°C. Pharmaceutical compositions containing these peptides are described, as well as methods for treating diseases, disorders, or conditions with inflammatory or autoimmune components and for downregulating immune mediator activity in subjects in need thereof.
The EPO-derived peptides are stabilized by techniques including the formation of disulfide bonds between sulfhydryl groups of amino acid residues within the peptide sequence and/or chemical addition of a small bicyclic molecule (such as d-biotin) to the peptide's N- or C-terminal ends. Specific amino acid sequences including cyclic peptides containing the sequence XAEHYS (SEQ ID NO: 31) with appropriate disulfide bonds are identified as responsible for the immunomodulatory and tissue protective functions.
The problem being addressed is that while the whole EPO molecule is known for hematopoietic and neuroprotective effects, long-term EPO therapy in non-anemic patients is limited due to overstimulation of erythropoiesis. Additionally, the neuroprotective and immunomodulatory domains within EPO are less stable than those responsible for hematopoiesis, limiting clinical application. Small isolated peptides derived from EPO have variable stability and biological activity, with linear peptides degrading upon storage. The invention solves this by providing stable, cyclic EPO-derived peptides that maintain immunomodulating, anti-inflammatory, and tissue protective activities without hematopoietic side effects.
Claims Coverage
The patent contains one independent composition claim and one independent method claim relating to treating inflammatory or autoimmune diseases. The claims focus on stable non-hematopoietic EPO-derived peptides with specific amino acid sequences and their therapeutic applications.
Composition comprising specific cyclic non-hematopoietic EPO-derived peptides
A composition comprising an erythropoietin-derived peptide, wherein the peptide amino acid sequence is selected from SEQ ID NO: 1, 3, 7, 9, 11, 12, 15, 17, or 30.
Method treating inflammatory or autoimmune diseases with stable EPO-derived peptides
Administering a therapeutically effective amount of the composition containing these EPO-derived peptides to subjects to ameliorate symptoms of diseases, disorders, or conditions having inflammatory or autoimmune components.
Stabilization of EPO-derived peptides
EPO-derived peptides being non-hematopoietic, cyclic, and stabilized by chemically adding a small bicyclic molecule to the N-terminal and/or C-terminal ends, a disulfide bond between sulfhydryl groups of amino acid residues, or both.
Administration routes and safety monitoring
Methods include administering the EPO-derived peptide compositions via oral, buccal, parenteral, nasal, rectal, or topical routes, with monitoring and maintenance of the subject's red blood cell indices at substantially normal levels during treatment.
Therapeutic applications for diverse inflammatory and autoimmune conditions
Use of stabilized EPO-derived peptides to treat acute cerebrovascular injury, acute spinal cord injury, acute brain injury, acute cardiovascular injury, arthritis, autoimmune diseases, demyelinating diseases, stroke, multiple sclerosis, neurological injuries, and immune-mediated inflammation.
The claims cover compositions of specific stable cyclic non-hematopoietic EPO-derived peptides and their therapeutic use for treating a variety of inflammatory and autoimmune diseases by administering effective amounts while maintaining normal hematologic parameters, with various routes of administration and stabilization methods including bicyclic molecule addition and disulfide bond formation.
Stated Advantages
The isolated stabilized EPO-derived peptides protect against tissue damage in neural and non-neural organ injuries.
These peptides exhibit non-hematopoietic biological activity and do not increase hematocrit levels or produce hematopoietic side effects.
Stabilization methods such as disulfide bonding and bicyclic molecule addition improve peptide biological stability and maintain efficacy during storage.
The peptides modulate immune-mediated inflammatory responses by reducing MHC class I and II over-expression, inflammatory cytokines, and antigen-specific T cell activity.
The peptides are broadly useful in treating diseases with inflammatory or autoimmune components without unwanted erythropoiesis stimulation.
Documented Applications
Treatment of symptoms of diseases, disorders, or conditions having inflammatory or autoimmune components including acute cerebrovascular injury, acute spinal cord injury, acute brain injury, acute cardiovascular injury, arthritis, autoimmune diseases, demyelinating diseases (e.g., multiple sclerosis), stroke, neurological injury, and immune-mediated inflammation.
Use in mouse models for experimental autoimmune encephalomyelitis (EAE) to reduce neurological impairment and inflammation.
Use in stroke models to improve neurological deficits following ischemic/reperfusion injury.
Treatment in spinal cord injury (SCI) animal models to improve neurological outcomes.
Potential application in arthritis (collagen induced arthritis model) and cardiac tissue injury (myocardial infarction) models to reduce inflammation and tissue damage.
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