Erythropoietin-derived short peptide and its mimics as immuno/inflammatory modulators
Inventors
Yuan, Rui Rong • Li, Wei Ping • Maeda, Yasuhiro • Dowling, Peter
Assignees
US Department of Veterans Affairs
Publication Number
US-8653028-B2
Publication Date
2014-02-18
Expiration Date
2026-05-01
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Abstract
The present invention 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 EPO-derived peptides and their mimics that protect against tissue damage in subjects with diverse neural and non-neural organ system injuries. These stabilized peptides demonstrate non-hematopoietic biological activity and can downregulate immune mediator activity. The invention also contemplates pharmaceutical compositions containing these peptides and methods for treating symptoms of diseases, disorders, or conditions having inflammatory or autoimmune components by administering the peptides while maintaining red cell indices at substantially normal levels.
The problem being solved originates from limitations of whole molecule erythropoietin (EPO) therapy, particularly in non-anemic patients with neurological injuries, where prolonged use leads to overstimulation of erythropoiesis and related side effects. Although modified forms or mutants of EPO have demonstrated neuroprotection without hematopoietic effects, small EPO-derived linear peptides had uncertain in vivo efficacy. The invention addresses the need for stable, efficacious short peptides derived from EPO that confer tissue protection and immunomodulatory function without undesired hematopoietic stimulation.
Claims Coverage
The patent includes two independent claims directed at isolated peptides and their pharmaceutical compositions emphasizing specific amino acid sequences and their use.
Isolated peptide consisting of SEQ ID NO: 7
An isolated peptide consisting solely of the amino acid sequence identified as SEQ ID NO: 7, representing a stabilized short peptide derived from EPO with non-hematopoietic biological activity.
Isolated peptide consisting of SEQ ID NO: 9
An isolated peptide consisting solely of the amino acid sequence identified as SEQ ID NO: 9, another stabilized short EPO-derived peptide with immunomodulatory and tissue protective properties.
Pharmaceutical compositions comprising isolated peptides and carriers
Compositions containing at least one isolated stabilized EPO-derived peptide (SEQ ID NO: 7 or SEQ ID NO: 9) formulated with pharmaceutically acceptable carriers in effective amounts for therapeutic administration, including combined peptide compositions.
The claims cover isolated peptides comprising specific stabilized EPO-derived peptide sequences (SEQ ID NO: 7 and SEQ ID NO: 9) and their pharmaceutical compositions, emphasizing their non-hematopoietic biological activity and therapeutic applications in inflammatory or autoimmune conditions.
Stated Advantages
The short stabilized EPO-derived peptides provide tissue protection against neural and non-neural organ injuries without stimulating erythropoiesis, avoiding hematological side effects associated with whole molecule EPO.
These peptides demonstrate long-term biological stability when stored at 4° C. or −20° C., especially in cyclic forms stabilized by disulfide bonds or by attachment of bicyclic molecules such as d-biotin.
The peptides modulate the immune-mediated inflammatory response by reducing MHC class I and II expression, lowering inflammatory cytokine levels, and suppressing antigen-specific T cell functions.
The peptides exhibit broad therapeutic potential, including neuroprotection in models of autoimmune encephalomyelitis, stroke, and spinal cord injury, with improved neurological outcomes and reduced clinical symptoms.
Documented Applications
Treatment of diseases, disorders, or conditions having an inflammatory or autoimmune component such as immune-mediated inflammation, autoimmune diseases, demyelinating diseases including multiple sclerosis, arthritis, acute cerebrovascular injury, acute spinal cord injury, acute brain injury, and acute cardiovascular injury.
Neuroprotection in central nervous system ischemic and traumatic injuries, including acute stroke and contusive spinal cord injury animal models.
Potential therapeutic use in non-neural organ inflammatory and immune injuries, such as rheumatoid arthritis and myocardial infarction.
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