Evelyn B. Kelley, Ph.D.

Proneuron Biotechnologies (Ness-Ziona, Israel) and Acorda Therapeutics (Hawthorne, NY) recently reported advances in neuroregeneration research. Each uses a unique approach but both are seeking to make a difference in treating these devastating injuries.

Every year in the U.S., there are about 12,000 new cases of spinal cord injuries, most of them related to car accidents and sports injuries. According to the Office of Health Care Information, spinal cord injuries are the most expensive of all hospital diagnoses, topping $56,800 for average charges for hospital stays.

A lifetime estimate of care is about $750,000 per patient. Spinal cord injuries are frustrating to physicians because the immune system does not repair these types of injuries and no drug or procedure is available to assist in regenerating damaged nerve tissues.

Proneuron Biotechnologies just received approval for a Phase I clinical trial of spinal cord cell therapy for newly injured paraplegic patients. "This is the FDA's first trial approval for a therapy aimed at regenerating nerve cells damaged by a complete spinal cord injury, a treatment that addresses a dire medical need," says Adrian Harel, Ph.D., company manager at Proneuron.

Proneuron's novel solution uses natural mechanisms. "We're not introducing outside, artificial molecules; we use cells to deliver a battery of natural molecules mimicking the mechanisms of the human body," says Valentin Fulga, M.D., Proneuron's director of regulatory and clinical affairs. Proneuron's technology is based on the research of Michal Schwartz, Ph.D., a professor at Weizmann Institute, Israel.

With a normal tissue injury, the body's natural immune system rushes to the site to heal, but with the central nervous system in humans and higher organisms, a built-in response prevents the immune system from doing its work. Dr. Schwartz thinks the mechanism evolved to protect the brain from the immune cells, which would disrupt its activity if they got into it. "An evolutionary advantage that protects the healthy be turns into a disadvantage in case of injury," says Dr. Schwartz. Simpler species, such as fish, can recover from CNS injuries.

Experiments with laboratory animals have shown the peripheral nerves do experience healing. Macrophages rush to the site of peripheral nerves; however, they have limited ability to help in healing the CNS injuries. Dr. Schwartz and his team activated the macrophages with damaged peripheral nerves tissue in a test tube and returned the macrophages to a damaged site in the CNS of paralyzed rats. The rats were able to regain partial use of their paralyzed legs.

Neurogeneration Procedure

Armed with the strong preclinical results based on Dr. Schwartz's studies, Proneuron's unique procedure of neuroregeneration recovers the macrophages from the person's blood, processes them, then injects them into the site of the injury. It takes about six to twelve months to show if the procedure is effective.

A major limitation of the procedure is that there is a narrow window, two weeks after the injury, when it must be used. After that, the damage is irreversible. A second limitation is that the procedure may not lead to a complete recovery. "We're sure we won't initially be able to grow 100% of the nerves," says Dr. Harel. However, with physical therapy and other care, any improvement in the state of the paraplegic is an advance. Currently, the nerve regeneration has been seen only in laboratory animals, but the Phase I trials will begin before the end of this year.

Meanwhile, Acorda Therapeutics won a Phase I Small Business Technology Transfer (STTR) grant from the National Institute of Health to research nerve generation. The $100,000 grant will fund an effort between the laboratory of Martin Grumet, Ph.D., at New York University Medical Center, and Acorda. The funded grant will be used to synthesize fragments of the protein Ll and test their ability to promote neurite outgrowth in culture.

Ron Cohen, M.D., president and CEO of Acorda, explains that L1 is a specialized neuronal cellular adhesion molecule (CAM), a protein that can transverse cell membranes. Present in embryonic CNS, it serves not only to connect cells but to help cells communicate. This protein has been shown to promote growth of axons by causing them to grow in a straight line. The protein L1, critical in the development of the fetal nervous system, disappears from the CNS at birth but continues to be present in the peripheral nervous system.

For example, if one cuts a nerve in the face or hand—if the nerve endings are not spread too far apart—the nerve can recover. "We believe L1 is a key molecule that regulates the growth of axons in the CNS, and we are using that molecule by reintroducing it in the adult to get that regeneration effect," explains Dr. Cohen.

The Ll protein has been shown to regenerate neurons and block CNS growth-inhibiting proteins. The protein has been shown to restore walking ability in laboratory animals with the injury. Dr. Cohen says that an important element is that the program will foster transfer of discoveries from academia to industry, where they may be delivered to a patient population.

The initial Phase I grant is intended to fund the first six months of work, which began in the summer. If the results look promising, they will apply for a Phase II grant, which can be more than a million dollars. If everything works out with the in vitro tests and the laboratory animal tests, it will be possible to be in clinical trials in twenty-four months.

Dr. Cohen comments that the research by his company, the announcement of the Proneuron trials and work by others in the field is positive. The fact that we are seeing these therapies getting into the clinic is a sign of how far the field has come." In 1991, the first reported study of treatment for spinal cord injuries were based on use of high doses of the drug prednisone. Today, more drugs are being tested, including Acorda's fampirodine for chronic spinal cord injuries.

"We are all eagerly awaiting the results of the human clinical trials," says Dr. Cohen, referring to Proneuron's activated macrophages. "In the next year, we expect at least two new potential therapies to get into the clinic." Dr. Cohen alluded to a clinical treatment at the University of Florida that involves implanting fetal nerve tissue in the spinal cord of people with severe spinal cord injury.

Beyond that, I would expect to see increasing numbers of spinal cord treatments actually getting into the clinic over the next five years and being tried in humans for the first time. Although some may not work, some will work, and we can count on seeing more spinal cord therapy over the next five years."