Nervous concerns, encouraging progress
Cell therapies provide new hope for treatment of CNS injuries
March 2003

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Jonathan B. Marder, PhD,
Proneuron Biotechnologies

Neurological disorders have traditionally presented modem medicine with some of its greatest unsolved mysteries. Millions of people worldwide suffer from acute or neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases, stroke, brain and spinal cord injuries, and other disorders considered incurable. New cell therapies, however, are now providing hope for victims of these devastating conditions.

Workings of the CNS
The nervous system is one of the most complex and enigmatic systems in nature. Nerves from all parts of the body are wired through the central nervous system (CNS), which consists of the brain, spinal cord and optic nerves. Normally, the CNS provides consciousness, intelligence, and the ability to sense the environment and move in it. However, when damaged by disease or injury, these functions are partially or fully lost, often causing severe disability. Thus, the CNS is well protected by a bony casing (skull and spine), and the blood-brain barrier that prevents pathogens and large molecules from entering. The CNS is also physiologically different from most other tissues, with biochemical and cellular mechanisms that limit tissue remodeling. Consequently, little or no recovery occurs in the CNS following trauma or disease.

Despite the complexity of the CNS, the basic structure and operation of the individual neurons are relatively well understood Neurons are designed to perceive stimuli from other nerves or sense organs and convert them into electrical pulses that travel via long projections called axons. The axons are electrically insulated by layers of myelin sheath, allowing the electrical impulses to travel quickly and efficiently. The electrical pulses are then converted into chemical stimuli that activate other nerve cells, or target organs such as muscles, through junctions called synapses.

CNS disorders are severe
CNS disorders result mainly from axon disruption, nerve cell death, myelin breakdown and biochemical abnormalities. These typically, form part of a complex cascade of events that cannot be treated effectively with conventional therapies.

In the case of physical injury to the head or spinal cord, there is a sudden loss of axon conductivity. The consequences are severe, dramatic and usually considered irreversible. Victims of spinal cord injury are often confined to a wheelchair, never again able to enjoy walking, jogging or dancing. The fortunate ones may be capable of using their upper limbs. The less fortunate may be completely paralyzed, unable even to breathe independently.

Cell therapies offer encouragement
Several cell therapy strategies offer considerable hope for the treatment of neurological disorders. One approach is to introduce new cells that directly replace the lost neurons. A second approach is to introduce new cells that have the potential to remyelinate new axons that regenerate spontaneously. A third approach, now in advanced clinical development, uses immune cells to overcome the natural inability of the CNS to heal itself.

Nerve cell replacement efforts
Nerve cells differentiate extremely early in development, and the mature human body seems to contain few undifferentiated cells that maintain the capacity to develop into new functional neurons. However, today there are several projects underway to develop sources of cells that do maintain the capacity to differentiate into neurons.

Embryonic stem cells are able to differentiate into all tissue types. Although the potential of stem cell therapy is very high, it is unlikely to become available in less than five to ten years because of distinct disadvantages. Firstly, there are serious ethical objections to the use of human embryonic tissue for research or clinical purposes. Secondly, the embryonic tissue would not be completely matched genetically to the recipient, thus raising the possibility of rejection.

Nevertheless, certain cell therapies have already been tested in humans. A cell therapy based on porcine fetal nerve cells is being developed by Diacrin, Inc. Phase I clinical trials are being conducted to test this product in spinal cord injury and focal epilepsy. Trials of a similar product to treat Parkinson’s disease failed to demonstrate efficacy.

An alternative approach is to use human cells that are already partly differentiated, i.e. committed to becoming nerve cells. Cultured human nerve cells are being developed by Layton Biosciences. Its product, LBS-Neurons, is derived from the human cancer, teratocarcinoma. The original cell line was developed at the University of Pennsylvania, where clinical trials are being conducted using LBS-Neurons to treat stroke victims. Initial clinical results show the treatment to be safe and beneficial. Animal experiments demonstrated that it may also restore neurological function in spinal cord injury

Myelinatlng cells in pilot trials
A very interesting approach involves the use of olfactory ensheathing glial (OEG) cells, the myelinating cells associated with the olfactory nerve. The olfactory nerve carries smell information from the nose to the brain, and is the only CNS nerve that continuously regenerates in adult mammals. Pilot clinical trials using OEG autografts to treat spinal cord injury patients began recently in Lisbon, Portugal and Brisbane, Australia.

Immune cells in nerve regeneration
Certain types of immune cells are relatively rare in the CNS, and their activities seem to be curtailed by a biochemical mechanism known as “immune privilege.” It thus seems radical to propose a role for immune cells in nerve regeneration. Furthermore, conventional wisdom holds that immune activity is something to be avoided in the CNS. However decades of research at the Weizmann Institute of Science, Rehovot, Israel, have suggested that the exact opposite applies after CNS injury. The observation was made that following non-CNS tissue injury, macrophages, a type of white blood cell, quickly arrive on the scene to clean up cell debris. Thereafter, these cells secrete different molecules and growth factors that promote a controlled inflammatory reaction and kickstart the wound healing process. While this process occurs in most tissues, including peripheral nerves, it does not occur in the CNS.

It was postulated that the immune privilege is needed to limit the cell turnover that typifies non CNS tissues - otherwise the CNS would be unable to perform its complex tasks because of continuous remodeling. However, once the CNS is damaged, immune privilege becomes a liability and overcoming it should facilitate nerve regeneration.

Following successful animal experiments, Proneuron Biotechnologies, Inc. conducted Phase I clinical trials on spinal cord injury patients, using macrophages isolated from the patients’ own blood and activated through a proprietary process. The first trial was conducted with regulatory approval from the US Food and Drug Administration. Final results are expected in a few months, but encouraging signs of neurological recovery have already been reported in some of the patients. Meanwhile, a second trial is being conducted in Brussels, Belgium, and Proneuron is making preparations for a large clinical trial in the US.

Expectations are high
The biotechnology industry is producing an increasing arsenal of new therapeutic strategies for CNS diseases and injuries. In the near future, cell therapies can be expected to revolutionize the treatment of neurological conditions, providing significant clinical benefits to millions of sufferers.