Ischemic stroke is an extremely debilitating condition that affects 800 thousand patients per year in the United States, resulting in 190 thousand deaths.  The patients that survive a stroke are often severely disabled and unable to function at the same level as before the event, creating both a financial burden on the healthcare system and a personal burden on the families that care for these patients.

Types of Stroke

There are two principal types of stroke:

• Ischemic
• Hemorrhagic

The principal difference is illustrated by the diagram at the right.  An ischemic stroke is similar to a heart attack in that some material, usually a blood clot, blocks one of the blood vessels that supply the brain.  When the blood supply is blocked, the brain tissue downstream from the clot is unable to remain oxygenated and that part of the brain dies.  Ischemic strokes account for more than 85% of all strokes.

Hemorrhagic strokes are potentially more dangerous and are caused by a rupture in the blood vessel itself resulting in bleeding into the brain vault.  Severe hemorrhages are immediately life-threatening due to the build-up of intracranial pressure, and frequently require a surgical intervention to alleviate the problem.

There is one highly effective treatment available for ischemic strokes and that is administration of a "clot busting" drug, the most popular of which is rhtPA (recombinant human tissue plasminogen activator).  This drug is a naturally occurring enzyme that helps to dissolve the clot and reopen the blocked blood vessel, thereby alleviating the lack of oxygen, with tPA dissolving an estimated 75% of stroke-causing clots within eight minutes after administration.  While tPA is highly effective for patients with an ischemic stroke, it comes with a few critical limitations:

• The drug is effective for ischemic strokes, but it will significantly worsen the intracranial bleeding for patients with a hemorrhagic stroke.  The early symptoms of both types of stroke are similar, so the patient must be evaluated by a CT or MRI scan to ensure what type of stroke they are having.  Smaller hospitals, especially in rural areas, may not have the necessary scanning equipment requiring the patient to be transferred to a hospital with the necessary diagnostic equipment.
• Patients with certain medical histories or who are on certain drug regimens are ineligible to take the drug.
• The drug must be administered within three hours after the onset of stroke symptoms.  While the FDA-approved drug label specifies a three hour window for administration, some institutions will extend the time up to four and one-half hours.  When tPA is administered beyond these time windows, survival of the patients is decreased, not increased.

Unfortunately, these limits mean that relatively few stroke patients receive tPA, and nearly all estimates reporting that fewer than 10% of stroke patients receive the drug.  Many strokes happen during the nighttime hours and the patient's condition is not discovered until morning, meaning that family members cannot provide an accurate time of onset and, even with an accurate time of onset, patients that are first treated at a remote hospital without the necessary diagnostic equipment will face delays that can extend the time beyond the three hour limit.  Patients who are identified in the field by paramedics and are then immediately transported by ambulance to a hospital designated as a "stroke center" have better chances of receiving the drug in a timely manner.

Cellular Therapy

 The principal risk of administering tPA outside the three hour window is hemorrhagic conversion, also called hemorrhagic transformation.   Some ischemic stroke patients, even those who do not receive tPA, will undergo a hemorrhagic transformation which turns an ischemic stroke into the more serious hemorrhagic stroke.  The risk of transformation increases beyond the three hour window, and many physicians are unwilling to take the risk rationalizing that after this period there is not much brain tissue that can be saved anyway.

Cellular therapy trials have obtained good results when administered to patients as late as 24 hours following the stroke.  There are a number of complex biological mechanisms that cells can address that tPA cannot, and the biological actions of cell therapy likely do not pose the same risk of triggering a hemorrhagic transformation because their anticoagulation process is fundamentally different from that of tPA.

Cascia has prepared a draft protocol for an ischemic stroke trial with a view to initiating a trial in the near future.