Who Can Participate

Proneuron is recruiting worldwide for patients to participate in a Phase 1 clinical trial of an experimental therapy for Complete Spinal Cord Injury. Patients who have suffered Acute Complete Spinal Cord Injury within the last 2 weeks, may provide their treating physician with the following eligibility information. Suitable patients will need to be transported to the clinical site to undergo the experimental treatment. The patient will be required to remain in the specific site for approximately 3 months for follow-up evaluation and rehabilitation.

Eligibility Criteria

1. Patients must fully conform to inclusion/exclusion criteria detailed below.
2. The patient must be less than 14 days when the treatment is administered.
3. An MRI showing the injury must be sent (preferably by e-mail) to Proneuron before the patient is accepted, or the radiologist could be in direct contact with one of the treating neurosurgeons to discuss details.
4. To ensure the patient's agreement to participate in the study, he/she will sign the Informed Consent form before he/she is accepted, and again before the procedure is performed.
5. The patient will return to his/her home country after 3 months.
6. During the following 9 months, the patient must be available for further assessments (performed in his/her home country by Proneuron's representatives)

Inclusion Criteria

• Age between 16 and 65.
• Male or non-pregnant non-lactating female.
• Individuals who have suffered a definitively diagnosed complete spinal cord injury
• A single spinal cord lesion in the segment from C6 to T11.
• The location of the injury can be determined by MRI as the region of the bony defect.
• The spinal cord injury is due to blunt, non-penetrating trauma.
• Can be treated before 14 days have elapsed after the injury.
• Informed consent obtained and consent form signed.

Exclusion Criteria

• Coma (that may interfere with the clinical evaluation of the patient).
• Penetrating spinal cord injury (to exclude potential risk of infection).
• Patient who received blood transfusions during the immediate period (three days) prior to the spinal cord injury (to exclude the potential of non-autologous monocytes in the harvested blood).
• Unstable multiple trauma that:
  • Requires continuous therapy (at the time of experimental treatment) with pressor drugs such as vasoactive amines.
  • Involves risk of septicemia.
  • Presents a surgical risk, such as liver, lung or kidney failure.
  • Causes the patient to be unable to tolerate harvesting of 200 ml blood.
• Severe concurrent medical disease (e.g., septicemia, HIV/HBV/HCV infections, insulin-dependent diabetes mellitus, systemic lupus erythematosus, multiple sclerosis, amyotrophic lateral sclerosis, malignancy).
• Chronic immunomodulating or cytotoxic drugs treatment.
• Anemia (hemoglobin lower than 10 gr. %), or after significant hematological disorder.
• History of severe neurological diseases or any other disease that may interfere with the neurological examination.
• Other severe neural injuries.
• Patient unlikely to be available for follow-up.

Autologous Activated Macrophage

Proneuron's cell therapy project is focused on the induction of regrowth of damaged nerve fibers within the CNS. The therapy targets an up-stream event, specifically macrophage activation at or near the site of injury. The Company's strategy is to induce nerve regeneration by enhancing the natural macrophage response in the injured spinal cord. This is achieved by direct implantation of activated autologous (patient's own) macrophages at the site of injury. To date, the therapy has been administered to 9 patients in a FDA approved Phase I clinical trial, showing promising initial efficacy results and a high safety profile. Four additional patients have been treated in a Phase 1b study in Belgium.

Proneuron's mission is to become the world leader in the field of spinal cord injury. Therefore, it regards the need to develop superior therapies for all types of spinal cord injuries as its ultimate target. The Company is continuously evaluating novel potential therapies, based on its scientific platform, that are showing promising effects in the treatment of spinal cord injury (complete and/or incomplete).

Macrophages are white blood cells that function as part of the immune system. Like other blood cells, they are produced in the bone marrow, move out into the blood, and then often onto various other body tissues. Macrophages play two several roles in the defense of the body:

• They engulf and dispose of foreign particles and debris from damaged tissues.
• They prepare pieces of the ingested material to induce specific immune responses in other types of white blood cells (B-cells and T-cells).
• Macrophages also influence other cells in the tissues where they reside, affecting their growth, development and physiological behavior.

Though normally thought of as a defense against pathogens such as bacteria and viruses, macrophages also play an important part in the repair of tissue after mechanical damage. Following injury, macrophages are the first cells to arrive at the wound site, where they ingest debris and mount an inflammatory response, the first stage of the healing process. While this response is normal and effective in most human tissues, it is almost absent in the CNS.

The CNS is isolated from the normal circulation of blood, thus rarely invaded by pathogens. Furthermore, the skull and spinal column shield the CNS against physical injury. Consequently, the nerve cells are protected and under normal conditions do not need replacing. This is just as well, as the intricate neural circuits laid down in the fetus and the newborn infant would not fare well if nerves were subject to continuous "rewiring" throughout life. However, the lack of a normal wound-healing response becomes a distinct disadvantage in the rare event of a catastrophic injury to the CNS. The damaged nerve cells are never replaced and the loss of function is permanent.

The goal of replacing damaged nerve fibers has long been regarded as one of the major medical challenges in medicine, and many different strategies have been tried. In research led by Prof. Michal Schwartz at the Weizmann Institute of Science, the wound-healing immune response was compared in nerves of different animals and systems. It was found that the absence of effective wound-healing is unique to the CNS of humans and other mammals, while peripheral nerves can heal in mammals and other animals, and even CNS nerves can heal in lower vertebrates such as fish. Poor wound healing in the CNS was attributed to a tissue-specific "immune privilege" mechanism that restricts the entry and activity of immune cells.

The idea behind macrophage therapy is to bring the natural wound-healing response to the spinal cord, so overcoming one obstacle to recovery. Prof. Schwartz and her team first tested this concept on rats with severely injured spinal cords. In the experiment, some animals were treated with macrophages that had been isolated from rat blood and activated in the laboratory by incubating them together with pieces of rat sciatic nerve (a peripheral nerve). Other animals were left untreated as a control group. Over the following months, around 60% of the treated rats recovered partial functional movement in their hind limbs. A positive treatment outcome of this degree is unprecedented in this type of experiment and was published in the July 1998 issue of the prestigious scientific journal Nature Medicine (Rapalino et al., 1998)