Lesanne Life Sciences, LLC - Stroke Diagnostics

Lesanne Life Sciences identifies and develops protein biomarkers for use in clinical diagnosis and drug development. The company's initial proprietary biomarker, the gamma isoform of the enzyme protein kinase C ("PKC gamma"), is in development for early diagnosis of ischemic stroke, which occurs when there is interruption of blood flow to the brain by a blood clot. In pre-clinical studies and a pilot proof-of-principle clinical trial, the company's scientific founders showed that PKC gamma is an early and predictable indicator of the occurrence of ischemic stroke. Lesanne's issued patents encompass the use of its novel biomarker for the detection of stroke and other ischemic brain injuries. The company plans to extend the use of the biomarker as a diagnostic of neurological ischemia associated with several other medical conditions, including traumatic brain injury ("TBI"), coronary artery bypass graft ("CABG") surgery, cardiac surgery, and coronary angiography and angioplasty.

Lesanne's core technology is based on a proprietary assay that can quantify the outcome of cerebral ischemia (reduction in flow of blood to the brain caused by a constriction or blockage of blood vessels) through detection of PKC gamma. This enzyme is found only in intact brain cells. Its presence in peripheral blood indicates the occurrence of damage to the central nervous system that was followed by transient breakdown of the blood brain barrier.

Premises for development of PKC gamma as a biomarker:

PKC gamma has been found in venous blood within 15 minutes following onset of a stroke.

PKC gamma is released immediately from cells following an ischemic event.

Software: Microsoft Office

Ischemia induces increased intracellular Ca2+ and diacylglycerol (DAG) which activates PKC gamma and stimulates translocation to the plasma membrane and release to extracellular space. The required increase in cytosolic Ca2+ is primarily provided by Ca2+ influx through voltage operated calcium channels or glutamate NMDAR channels, and the required DAG signal is primarily generated by the activation of glutamate mGluRs.

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Lesanne plans to develop its PKC gamma assay in a diagnostic test format that provides a rapid, qualitative assessment of the occurrence of stroke for use in triage in emergency settings. The diagnostic could be used to recognize an ischemic event prior to the formation of an infarct and the associated spreading penumbra. Clinicians would use the diagnostic as a prognostic tool for determining appropriate treatment regimens.

In addition, the company intends to develop a quantitative diagnostic test for assessment of the level of damage to the CNS system. This diagnostic would be used as one means of quantifying the extent of damage to the blood brain barrier. It also might be used to determine if a formed clot has dissolved following infusion treatment with TPA. In addition, the quantitative diagnostic could be used to detect the occurrence of subsequent ischemic events while patients are being treated in a hospital setting.

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Incidence and Prevalence

Stroke is the third leading cause of death in the United States after heart disease and cancer. It is a major cause of disability among adults and a major factor in precipitating or exacerbating dementia in elderly individuals. The incidence of stroke is rising worldwide. Almost five million people in the U.S. have experienced a stroke and approximately 700,000 new cases are reported each year in the U.S. The World Health Organization reports that stroke is responsible for about 5.5 million annual deaths and is the third most common cause of death worldwide.

Lesanne Diagnostic for Stroke

There are currently two FDA-approved approaches for the treatment of stroke:

(1) The current standard treatment for stroke caused by a blood clot in the brain involves administration of a clot-dissolving drug, TPA, which must be administered within the first three and possibly up to six hours following the occurrence of a stroke. However, prior to administering that drug to a patient, a physician must first be certain that the stroke was caused by a clot and was not the result of a hemorrhage, because administration of TPA can result in increased bleeding. Over 80% of strokes are ischemic (interruption of blood flow by a blood clot), and the remainder of strokes are hemorrhagic.

(2) Concentric Medical, Inc. has received recently approval by the FDA for the first medical device for the physical removal of clots from blood vessels within the brain of patients who have suffered an ischemic stroke. The "Merci Retriever System" is anticipated to increase the time window for treatment for some patients.

Most individuals who suffer a stroke show evidence of one or more of the following symptoms: headache, dizziness, sudden weakness or numbness of the face arm or leg, sudden trouble speaking or walking or loss of balance. Often these signs are not correlated by those individuals or family or friends as being symptomatic of a stroke, and as a consequence many people wait too long prior to seeking medical assistance. Furthermore, emergency personnel do not have readily available tests to allow them to accurately diagnose the occurrence of stroke and thus patients often are not triaged correctly in the ambulance or emergency room. Delayed diagnosis, imaging, and subsequent treatment can result in neurological impairment and even death for stroke patients. Estimates are available indicating that the percentage of stroke victims who are diagnosed expeditiously and subsequently treated with tPA could increase to about 20% from the current level of about 4% if they were to be diagnosed and brought rapidly to stroke centers rather than to nearest hospitals.

Traumatic Brain Injury

Traumatic Brain Injury is a major cause of morbidity and mortality in the U.S. There are more than 1.1 million emergency room visits, 50,000 deaths and 235,000 hospitalizations due to TBI. The leading causes of TBI include: falls, motor vehicle accidents, bodily strikes, sports injuries, or blast injuries (particularly in war zones).

USA today reported on March 4, 2005, that "A growing number of U.S. troops whose body armor helped them survive bomb and rocket attacks are suffering from brain damage... It is the type of injury that some doctors say has become a signature wound of the Iraq War." It has been estimated that almost two-thirds of wounded in action injuries were caused by bombs, grenades, landmines, and missiles. Soldiers having TBI show impairment in brain function, including memory loss, language impairment, delayed reaction time, mood and behavior changes, depression/anxiety, and emotional out-bursts.

The impact of TBI on soldiers at war is enormous, and the potential impact of disorders resulting from TBI for soldiers returning home threatens to become a significant burden to the U.S. health care system.

Lesanne Diagnostic for Traumatic Brain Injury

Lesanne's diagnostic is applicable for the diagnosis of traumatic brain injury. Mechanical strain and increased intracranial pressure results in ischemia and neuronal damage. Those damages result in rapid membrane depolarization, rapid rise in Ca2+, glutamate excitotoxicity, and the release of PKC gamma from the CNS. Use of Lesanne's diagnostic in situations where TBI might occur, such as on the battle field or at certain sporting events, could represent a major advance in early detection which in turn should result in early treatment and a reduction in the number of consequences of TBI such as epilepsy, Alzheimer's disease, Parkinson's disease, stroke, depression, and anxiety.

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Coronary Artery Bypass Graft Surgery

Coronary artery bypass graft surgery is a frequently used procedure (500,000 per year in the U.S.) to reduce angina and stabilize ventricular function. CABG surgery presents a significant risk for cerebral injury. Severe neurological consequences such as stroke or transient ischemic attacks occur in up to about 6% of patients. In addition, it has been reported that 33% to 83% of patients have neuropsychological impairment and cognitive defects after CABG surgery. A very recent study indicated that CABG surgery using extra-corporeal circulation resulted in 96% of patients exhibiting cognitive dysfunction at the point of hospital discharge. When blood flow ceases to any part of the brain, even temporarily, neuronal function is impaired and a complex cascade of events is initiated that can permanently damage neurons during the ensuing few hours. The ability to identify such stoppages or interruptions in blood flow and to manage subsequently the decreased perfusion or micro emboli would diminish greatly ischemia-induced neuronal damage that might contribute to subsequent cognitive decline following CABG surgery. Although the severity of many forms of cognitive dysfunction appears to decline over the course of time, a significant number persist and some investigators believe trigger more serious disorders such as Alzheimer's and Parkinson's diseases.

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Lesanne Diagnostic for CNS Ischemia from Coronary Artery Bypass Graft Surgery

A rapid blood test for ischemia of the CNS would have great value during CABG surgery or for monitoring transient or diffuse ischemia that develops from the surgical procedure. Patients also could be monitored for several days following surgery. Ischemia-induced break-down of the blood brain barrier can be established through detection of PKC gamma in peripheral blood. Intracellular levels of PKC gamma are expressly activated (within milliseconds) by an ischemic event. Activation of PKC gamma is not a downstream event, but rather the enzyme is released from the CNS in direct response to an ischemic event and therefore can serve as a quantitative surrogate for the occurrence of ischemia.

Drug Development

Lesanne's diagnostic can be used for quantifying severity of ischemia in various animal models of stroke (such as Middle Cerebral Artery Occlusion). The diagnostic should aid in the identification of lead candidates that specifically target cellular injury resulting from stroke or ischemia. In addition, the diagnostic can assist in the selection of drug candidates to be driven into Phase I clinical development and thereby increase the chance for success in clinical trials for drugs to treat certain CNS conditions. Many stroke therapeutics have failed in development because of the inability of clinicians to be able to stratify patient populations. Stroke is currently diagnosed using several techniques, including: a short neurological examination (NIH Stroke Scale Score), blood tests, CT scans, MRI scans, Doppler ultrasound, and arteriography, all of which are independent measures of neuronal damage but not ischemia. The most important contribution of the company's diagnostic for clinical development of stroke therapeutics is affording investigators the capability of choosing a homogenous population of patients for specific clinical trials. Use of more narrowly defined patient populations should allow smaller studies to be conducted and thereby increase the likelihood that such studies will be successful.

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