The cure is worse than the disease.
The old adage "the cure is worse than the disease" regrettably is true with respect to the body's own response to injury. In an attempt to stop the spread of tissue damage from a localized, primary site of insult following a catastrophic event, the body needlessly targets a large area of tissue surrounding the injury for destruction. This leads to greater impairment and to a slow, limited recovery.

This overprotective, natural defense mechanism evolved long ago to protect the individual from succumbing to secondary damage from the primary event. The secondary damage of cells and tissues is in fact the reason for slow and incomplete recovery from illnesses and injuries like stroke, heart attack or spinal cord trauma.

Therefore, this secondary damage of cells and tissues serves no survival function and is in fact the reason for slow and incomplete recovery from such illnesses and injuries.

Warren Pharmaceuticals has identified novel proteins named tissue protective cytokines (TPCs) with potent protective effects that diminish and reverse the underlying cellular damage in these significant diseases.
The zone of reversible damage previously off limits to interventional therapy is now accessible, even across the normally impenetrable blood-brain and blood-retina barriers. Tissue Protective Cytokines have the property of traversing normally restrictive barriers in various parts of the body that exclude access by drugs. TPCs for delivery to the brain or eye, for example, can be easily administered by intravenous injection.

First Generation Tissue Protective Cytokines.
Erythropoietin (EPO), the hormone stimulating the production and differentiation of red blood cells, and it is widely used for treating anemia of renal disease or anemia induced by chemotherapy.

In animal models, Warren scientists have generated evidence that EPO also protects tissues throughout the body against excessive cell death as a consequence of severe diseases and injuries. These findings have been confirmed by a number of independent investigators. A clinical trial conducted in Germany showed beneficial neuroprotective effects of EPO in patients when administered within 8 hours of stroke, confirming tissue protection by EPO in man.

In order to avoid hematopoetic effects of EPO, Warren Pharmaceuticals sought to separate the blood cell stimulating and tissue protective activities of EPO.

Second generation EPO derivatives.
By extensively studying the structure-activity relationship of EPO and its derivatives, Warren scientists were first to elucidate the two biologically distinct functions of EPO through its interaction with two very different types of receptors. This discovery led Warren to engineer a variety of second generation EPO molecules that possess potent tissue protective properties without stimulating red blood cell production, making therapy potentially useful in a large number of disease areas. Warren subsequently has pioneered the preclinical development of cytokine technology in tissue regeneration and protection for the treatment of devastating injuries and diseases including acute kidney failure, heart attack, stroke, spinal cord injury, and acute macular edema.

A novel cell surface receptor complex identified by Warren scientists comprises one classical EPO receptor (EPOR) subunit and a pair of beta common receptor (ßCR) subunits. Interaction of this complex with a Tissue Protective Cytokine induces cellular changes that resist the damaging effects arising from local injury or disease processes. Warren TPCs are selective and have no affinity for the erythropoietic receptor. Click here to continue reading about the biological activities and efficacy of Tissue Protective Cytokines

Understanding the Body's Response to Injury
From the perspective of evolutionary selection, this tissue response to injury evolved as an effective mechanism for reducing the risk of infection and of protecting the surrounding healthy tissue from additional injury. Several pathways are involved in this tissue response to injury.

Cutting losses. First, the blood flow to the damaged area is constrained in order to minimize blood loss, maintain blood pressure and reduce oxygen and nutrient flow to the effected tissue. Within hours, certain tissue factors, including tumor necrosis factor (TNF), are released by the damaged cells into their surroundings. These factors attract macrophages, white blood cells specialized in cleaning up damaged tissues. Furthermore, the nutrient flow between affected and healthy tissue is interrupted in order to isolate the injured area. As a result, cells within the affected region begin to die, predominantly via programmed cell death, or apoptosis. Moderate inflammatory reactions ensue, helping to clean up the damaged tissue. As the inflammation abates, repair mechanisms become activated and ultimately lead to the formation of a scar. Tissue-specific effects. Although the temporal occurrence of these pathways is principally observed independently of tissue and injury type, tissues have developed highly specialized and specific responses to certain injuries. For example, subarachnoid hemorrhage (bleeding in the brain often leading to stroke) is associated with an immediate and pronounced vasoconstriction of cerebral vessels, as an attempt by the body to diminish the extent of bleeding. On the other hand, a thromboembolic coronary event (leading to a heart attack) induces little vasospasm but rather results in an extensive inflammatory response within the ischemic area, accelerating the removal of necrotic tissue and scar formation. Rapid formation of a strong scar is imperative in the mechanically stressed cardiac tissue to avoid the potential complications of cardiac rupture and aneurysm formation. Murder by death. Apoptosis, programmed cell death and more dramatically known as cell suicide, is a critical component of the human tissue injury response. In apoptosis, a genetic program leads to degradation of nuclear DNA, followed by shrinking and fragmentation of the nucleus. In contrast to cellular necrosis, which is an irreversible cell death typically found at the epicenter of a tissue injury, apoptosis occurs in potentially viable cells, typically located at the periphery of the injured area. Surviving neighboring cells and macrophages quickly absorb the shriveled corpses of apoptotic cells, limiting the extent and degree of the secondary inflammatory response associated with cell damage and death. Within hours of the injury, additional inflammatory cells migrate to the injured area and further promote the removal of dead cells. Eventually, new cells are formed from the surrounding healthy tissue or from progenitor (stem) cells, and a scar is formed.

Bigger is not better.
The demarcation of the damaged area from healthy surrounding tissue through apoptosis, as described above, may be life saving in the absence of modern therapeutics and overall medical care. However, it has been shown in numerous animal injury and disease models involving apoptosis that the pharmacological reduction of apoptosis results in improved functional and histomorphometric outcomes.

Therefore, it is quite likely that in today's health care environment the salvage of potentially viable cells by anti-apoptotic therapeutics may be a highly cost-effective approach to the treatment of injuries and illnesses associated with a high level of apoptosis.

The potential benefit would be particularly important in vital tissues regenerating at a very slow rate, such as cardiac myocytes, retinal photoreceptors and neuronal cells. Recent scientific work demonstrates the presence of apoptosis in a wide range of acute and chronic human illnesses.

Myocardial infarction (heart attack), chronic heart failure, age-related macular degeneration, diabetic retinopathy, diabetic neuropathy, Alzheimer's disease, multiple sclerosis, and Lou Gehrig's disease are all disorders in which apoptosis appears to be an important pathogenic factor. For example it has been shown that in chronic heart failure, cardiac cells undergo apoptosis at a rate about 200 times greater than in normal heart tissue.

Reducing these secondary consequences of damage to tissues surrounding the primary sites of disease or injury would reduce the overall degree of impairment and increase the potential for recovery.

These indications represent significant patient populations and disease areas with limited therapeutic options.

Proof of
Principle in
Disease
Models

Preclinical studies conducted to date in numerous disease models have shown dramatic improvements in tissue viability and reduction of severity of disease or disability after administration of TPCs. Along with a positive overall impact on the disease model, when examined at the various cellular and tissue levels described above, there is a corresponding positive effect on cell survival by inhibiting apoptosis, reducing inflammation and increasing perfusion of tissues in the at-risk zone surrounding the primary site of disease or injury. This extensive compendium of in vitro and in vivo data strongly supports the future clinical potential of Warren Pharmaceutical's TPCs to positively impact the treatment of many diseases.

The table below represents only a subset of positive efficacy studies in disease models. Click on a study to obtain expanded information on design and outcome.

Therapeutic Area: Cardiovascular	Human Disease Myocardial Infarction: Ischemia-reperfusion Disease Model Coronary artery temporary ligation Brief Summary of Results Significantly improves cardiac function TPCs improve cardiac function, after one hour of ischemic injury, as measured by left ventricular end-diastolic pressure, one week later. Click to view larger chart
Therapeutic Area: Eye	Human Disease Macular Degeneration: Ischemia-reperfusion Disease Model Pressure-induced and light-induced retinal injury Brief Summary of Results Increases sensitivity to light as measured by electroretinogram TPCs protect retinal tissue in a rat glaucoma model Click to view larger chart
Therapeutic Area: Brain/ Central Nervous System	Human Disease Ischemic Stroke Disease Model Middle cerebral artery occlusion Brief Summary of Results Reduces extent of and severity of damage to tissue surrounding blocked artery TPC administration in a rat ischemic stroke model reduces damage to surrounding brain tissue whether given 1.5 or 4 hours after induction of stroke TPCs protect brain cells from neurotoxin-induced death Click to view larger chart Human Disease Spinal Cord Injury Disease Model Spinal cord compression Brief Summary of Results Improves recovery of motion and sensation following injury and stimulates recruitment of stem cells. TPC administration promotes neuron survival in an injury model TPCs recruit stem cells to region of compressive injury; Stem cells appear red. TPCs improve motor score in a spinal cord injury model whether given immediately or 5 days after injury Click to view larger chart Human Disease Chronic Multiple Sclerosis Disease Model Experimental allergic encephalitis Brief Summary of Results Dose-responsive improvement in motor score TPCs in a dose-responsive manner reduce the severity of symptoms in a rat multiple sclerosis model. Click to view larger chart
Therapeutic Area: Peripheral Nervous System	Human Disease Peripheral Neuropathy Disease Model Temporary compression of sciatic nerve Brief Summary of Results Dose-responsive improvement in sensory sensitivity index Dose-response effect of TPCs on the severity of neuropathy in a model of crush injury to the sciatic nerve in the rat. Click to view larger chart Human Disease Diabetic Neuropathy Disease Model Diabetes model Brief Summary of Results Dose-responsive improvement in motor score TPC administration prevents loss of skin sensory nerve fibers in a disease model. Click to view larger chart
Therapeutic Area: Kidney	Human Disease Ischemic Renal Failure Disease Model Temporary occlusion of vessels Brief Summary of Results Prevents ischemic damage to renal tissue TPC prevents structural damage to kidneys after ischemic injury. Click to view larger chart

Publications