EXECUTIVE SUMMARY

Erythropoietin-Derived Short Peptides

for the Treatment of Central and Peripheral Nervous System Diseases

SUMMARY:  Siuta Consulting has been retained by the University of Medicine & Dentistry of New Jersey (UMDNJ) to identify partners for novel stabilized erythropoietin (EPO) derived short peptides discovered by Drs. Rui Rong Yuan and Peter C. Dowling in the Veterans Administration Medical Center at UMDNJ.  These peptides have been shown in vivo to protect against tissue damage in mouse models of experimental autoimmune encephalomyelitis (EAE), acute stroke, acute spinal cord injury and brain injury by reversing and/or reducing the manifestations of the associated disease.  They have 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. 

BACKGROUND:  EPO is a 165 amino acid glycoprotein hormone that was initially identified as a hematopoietic growth factor and has been used extensively for the treatment of anemia.  Whole molecule EPO has received considerable attention recently because it may have broad neuroprotective capabilities following CNS injury.  Therapeutic effects of exogenously administered EPO on several forms of neurologic injury, including occlusive cerebral vascular disease, acute brain trauma, epilepsy, and an autoimmune model of demyelinating disease, experimental autoimmune encephalomyelitis, have been tested and the degree of neurological impairment was significantly reduced.  However, long-term EPO therapy remains significantly limited in non-anemic patients with neurological injury because EPO may overly stimulate erythropoiesis. 

TECHNOLOGY:  The hematopoietic effect of EPO is mediated by binding and inducing dimerization of two molecules of the EPO receptor (EpoR) on the cell surface.  Studies on structure-activity relationships of EPO have identified regions and amino acids essential for binding to the EpoR, suggesting that neuroprotection mediated by EPO might not occur through conventional interaction between EPO and classic EpoR.  The common β receptor (βcR) or CD131 has been proposed to be a key subunit associated with the EpoR that is responsible for EPO mediated non-hematopoietic effects. 

Based upon the belief that there are at least two distinct functional peptide domains co-existing within the whole EPO molecule and that sequences and/or structures within the EPO-derived peptides will dictate their biological functions (erythropoiesis or tissue protection), Drs. Yuan and Dowling have prepared small EPO-derived peptides that have been shown to have neuroprotective and immunomodulatory activity.

A library of stabilized isolated EPO-derived peptides comprising about 7 to 25 amino acids in length has been created and tested in vitro and in vivo for therapeutic efficacy.  These EPO-derived short peptides are highly protective in mouse models of EAE, acute stroke, acute spinal cord injury and brain injury by reversing and/or reducing the manifestations of the associated disease.

The following two in vivo experiments demonstrate these results: 

Improvement of neurological deficit in acute spinal cord injured mice:

In this animal model of contusive spinal cord injury, all animals developed complete hind limb paralysis immediately after impact.  During a three day observation period, the sham-treated control animals remained severely paralyzed whereas the treated animals showed substantial improvement in neurological deficit with two of three animals regaining the ability to walk.

Improvement of neurological deficit in an intraluminal occlusive stroke mouse model:

In this animal model of ischemic stroke, all animals developed mild to moderate unilateral hemiparesis affecting fore and hind limbs and showed reduced mobility.  After a 72 hour reperfusion period, the sham treated animals either remained paralyzed or showed increase neurological deficit.  A 25% mortality rate was encountered in the early course of the disease in the sham control group.  In contrast, animals treated with the EPO derived peptide showed substantial improvement in neurological deficit with zero mortality.

PUBLICATIONS:  W. P. Li, Y. Maeda, R. R. Yuan, S. Elkabes, S. Cook and P. C. Dowling, Beneficial Effect of Erythropoietin on MOG-Induced Experimental Autoimmune Encephalomyelitis (EAE), Annals of Neurology, 56, 767-777 (2004)

PATENT STATUS:  International Patent Application WO2007052154 was published on  May 10, 2007 and claims priority to United States Provisional Patent Application No. 60/676,592 that was filed on April 29, 2005.

LICENSE TERMS:  An exclusive license is available.