Veterans Affairs

EPO-derived peptides protect against brain tissue damage

In addition to their neuroprotective qualities, these isolates may have benefit against autoimmune disorders other inflammatory diseases

Medical & Biotechnology

Erythropoietin. Short peptides of this protein have dramatic therapeutic effects against multiple diseases. Wikimedia Commons

Scientists at the U.S. Department of Veterans Affairs (VA) have recently identified and characterized small EPO-derived peptides with different biological functions having neuroprotective and immunomodulatory activity. The patented technology is available via patent license agreement to companies that would make, use, or sell it commercially.

Erythropoietin (EPO), a 165 amino acid glycoprotein hormone, was identified initially as a hematopoietic growth factor and has been used extensively for the treatment of anemia in humans. Whole molecule EPO received considerable attention recently because it may have broad neuroprotective capabilities following CNS injury. Therapeutic effects of exogenously administered EPO on several diverse forms of neurologic injury, including occlusive cerebral vascular disease, acute brain trauma, epilepsy, and an autoimmune model of demyelinating disease, experimental autoimmune encephalomyelitis (EAE), have been tested and the degree of neurologic impairment was significantly reduced.

However, long-term EPO therapy remains significantly limited in non-anemic patients with neurological injury because EPO treatment may overly stimulate red blood cell production. To overcome this concern, EPO therapy would have to be limited to very short term use.

Making a leap towards a marketable EPO therapeutic for brain injuries and other diseases, VA scientists have developed a library of stabilized, isolated EPO-derived peptides comprising about 7 to about 25 amino acids in length and tested in vitro and in vivo for therapeutic efficacy. These short EPO-derived peptides are highly protective in mouse models of EAE, acute stroke, acute spinal cord and brain injury as well as arthritis by reversing and/or reducing manifestations of the associated disease.

The peptides protect against tissue damage by modulating the immune-mediated inflammatory network – reducing major histocompatibility complex (MHC) class I and class II over-expression, reducing inflammatory cytokines, and by suppressing antigen-specific T cell function in peripheral lymphoid tissue and brain tissue and in in vitro tissue culture assays. The addition of a small bicyclic compound, such as d-biotin, to the N- or C-terminal of EPO linear peptides, increases stability without hampering their biologic activity.

These newly developed small peptides hold immense potential for direct clinical application in the treatment of central and peripheral nervous system diseases associated with injury including demyelinating diseases, traumatic injury and stroke. Since the beneficial effect of these peptides is not limited to neural tissue organs, they are broadly useful in the treatment of inflammatory/immune injury to non-neural organs of the body.

Lead compounds, JM4; JM5; and JM7, stabilized, cyclic peptides derived from the first loop of EPO, have been evaluated in vitro and in vivo. They have shown good efficacy in animals (EAE and TBI models) and the preliminary side effect profile is highly favorable compared to whole molecule erythropoietin.

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