More MS news articles for October 1999

Holy grail of neuromedicine

Sunday, October 24, 1999    15 Heshvan 5760  Updated Sun., Oct. 24 18:14


(October 24) -- Proneuron's cell therapy treatment may help partially heal spinal cord injuries - a feat considered medically impossible --

Adrian Harel, company manager of start-up Proneuron Biotechnologies, begins with a warning. "We have to make sure we don't raise false hopes," he says. "We can't help people already suffering from spinal cord injuries, and our treatment isn't actually ready yet."

This might seem a strange way to start an interview but Harel is speaking from experience. Over the last few years the company has been deluged with letters and calls from people suffering paralysis after injuries to their central nervous system (CNS) who see in Proneuron some kind of miracle cure. One wealthy Italian even went so far as to offer to sell off all his belongings and plow the money into Proneuron in exchange for a promise that the company would just try out its experimental treatment on him.

Proneuron, however, is very far from offering a cure. It does, however, offer an important ray of hope. The company has developed an innovative cell therapy that could help people who suffer an injury to their CNS, which includes the brain, the spinal cord and optic nerve, regain some of their ability to move. It has further ramifications for immune-related disorders such as multiple sclerosis, Parkinson's disease, Alzheimers and glaucoma.

If this works, it will mean a breakthrough in medical science. Until now there was no treatment for people suffering paralysis after an injury to their spinal cord or brain.

Unlike other parts of the body, the CNS cannot heal itself and once it is damaged it will never recovery. As Prof. Michael Belkin, director of the opthalmic technology laboratory at Tel Aviv University in Tel Hashomer, says: "This could revolutionize the fields of neurology and opthalmology. The text books will have to be rewritten and all clinical procedures will be changed."

So far the Rehovot company, which has received $7 million in venture capital funding, has demonstrated its technology on rats. It is now beginning its first clinical trials on humans at two Israeli hospitals and Harel believes that if all goes well, the treatment could be out on the market in three years.

Proneuron was founded in September 1996 and is based on an idea developed by Professor Michal Schwartz of the Weizmann Institute of Science, who remains the company's chief scientist. Seed capital of $3.5m. came from the Hudson Investment Group in Los Angeles. A further $3.5m. investment was made in July last year. The investors in the second round were venture capital funds Nessuah Zannex, Lapid Medical Ventures, Polaris and Infinity.

The company was initially incorporated in the US but this, as Harel admits, is only a virtual office. The company's 600 sq. meter headquarters are in the Rabin Science Park, next door to the Weizman Institute.

Forty-two-year-old Harel - one of Schwartz's Ph.D. students who had gone on to study business - was invited to run the company.

For the last three years Proneuron, which now employs 21 people - five of whom are doctors - has devoted itself completely to research and development. The company's main focus is on disorders and problems in the CNS.

In the body the nervous system is divided into two parts, the CNS and the PNS, the peripheral nervous system, which is the rest of the body's nervous system.

The CNS is separated from the PNS and has immune priviledge which means that if the body is injured, the inflammation that follows does not reach the CNS. This protects the brain which has millions of fragile but vital connections that could easily be disrupted and destroyed by any inflammation.

The only problem with this is that CNS has no regeneration capacity. Once damaged the cells cannot regrow. If someone suffers a spinal injury or surgery on a brain tumor goes wrong, the body cannot heal itself but remains damaged for life. In the PNS, which does not have immune priviledge, the nerves have the capability to regrow and become functional again.

"We need inflammation for regrowth and regneration," explains Harel. "It brings in white blood cells, gets rid of dead cells and attacks any foreign bodies. Basically it cures the body. In the CNS, however, this doesn't happen. There's no inflammation and no regeneration."

Proneuron's solution is to induce CNS regeneration so that someone with an injury or disorder of the CNS will not completely lose his ability to function.

What makes Proneuron's approach to this field unique, according to Harel, is that it isn't trying to develop a chemical, an agent or a drug to try to heal the body, but is using the body's own resources to help it cure itself.

"We believe the ability to regenerate or to heal is part of our body and we just need to direct it properly," says Harel. "Hippocrates said 'natural forces within us are the true healers of disease', and this sums up what we are trying to do. Hopefully, the body can cure everything, we just have to find out how."

This might all sound a bit New Age and certainly the idea hasn't been received well by some areas of the medical establishment who Harel admits, greet the notion with a great deal of scepticism and raised eyebrows.

However, Harel insists that the company pursued this idea not from any desire to bow to popular opinion, but because they found, in animal models at least, that it works.

"The body usually heals itself, except in the central nervous system," adds Belkin, a member of Proneuron's senior advisory board,dismissing the medical doubts. "Every great breakthrough has its detractors at the beginning."

Basically what Proneuron is trying to do is take cells from a patient's PNS and inject them into his spinal cord to cause a healing inflammation. Using the body's own cells means less side effects than drugs since they are part of the body's natural defense system, it also means they are more effective.

"When you put a pill in your mouth there's a burst of chemicals in your body. You have a huge concentration of chemicals for one to two hours and then it goes down," explains Harel. "When you put cells into the body you have a small factory producing many chemicals over an unlimited period of time. The cells know how to act and they secrete the right chemical at the right time and in the right concentration. And they can vary their behavior throughout the healing process so that you don't have to use several different drugs in different concentrations. The cells respond directly to the needs of the body."

In addition cells can be positioned where they are needed within the body, while drugs flood the whole body.

Proneuron has three projects on the go, two in cell therapy and one a drug therapy. About 90 percent of the company's financial resources and personnel are devoted to the neuroregeneration project, which received US Food and Drug Administration (FDA) approval just a few weeks ago and is the company's most advanced project.

This project uses active macrophages - a type of white blood cell, which are the first to come on the scene when there is an injury or infection in the PNS. If there is an injury in the CNS, these appear but they come too late and in too small a quantity to provide any help.

Proneuron has found a way to extract these from the blood supply and properly activate them in the CNS so they can do their job there.

Experiments on rats have shown that those who receive the cell therapy after a spinal injury has left them paralyzed in the back legs and tail, can, within two weeks of the injury regain some kind of mobility. Both the tail and the back legs regain about 50 percent of movement and coordination and the animal can support itself to a certain extent on its back legs.

The downside of this discovery, however, is that they found there could only be a recovery if the rat was treated within the first two weeks after the injury. After this the window of opportunity closed.

All these trials have done is prove the theory. Harel acknowledges that there is no way they can calculate what effect this treatment will have on human beings. "Humans have willpower and want to improve, they also undergo physiotherapy which we don't give rats," says Harel.

But, says Harel, even minimal improvement is better than nothing. One of the most famous people suffering from a spinal cord injury is actor Christopher Reeve. Today he needs to be connected to a respirator around the clock and has lost all movement below his neck. "If our treatment just got him off the respirator you can imagine the improvement in his quality of life," says Harel.

The immediate market for such a treatment is relatively small. About 40 people out of one million suffer a spinal cord injury in the US every year, or about 12,000 people. Of these only 5,000 are candidates for the therapy.

Not many, but what you have to remember is they will spend the rest of their lives in wheelchairs and their life expectancy after the injury is about 27 years. The cost per patient, whether they are partially or completely injured, is an average of $772,000, with costs rising to $2m. depending on the extent of the injury. This sum doesn't include loss of income or compensation.

Proneuron's treatment costs about $50,000. "This is a small amount compared to the reduction in costs we will create," says Harel.

The company has now received permission from the Ministry of Health to begin phase one clinical trials at Tel Hashomer and Beilinson Hospitals at the end of the year. Usually in the first clinical trials the company treats healthy volunteers to make sure there are no damaging side effects. In this case, however, the trials will begin immediately on patients who come to the hospital with an injury.

Because this therapy is a natural one that uses the body's own cells, Harel believes that it can be out on the market in less time than a drug. Drug development can take between 12 to 17 years, and can cost between $400m. to $600m.

Harel estimates that this treatment could be out in 2002 and will be substantially cheaper because it will only have to prove the treatment works on a few dozen patients rather than hundreds as in the case of drug therapy.

The company's second project is neuroprotection, a treatment based on activated T-cells (another form of white blood cell) that help protect non-injured neurone cells. It is designed for partially injured patients.

When someone receives a partial injury to the CNS it causes an initial wave of cell death. Following this, however, come second, third and even fourth waves of cell death, as the initial dead cells spill out harmful chemicals and shut down vital connections.

A patient might initially be able to move his legs but within two weeks will be completely paralyzed. If the T-cells are implanted in the CNS in those all-important first two weeks, they Proneuron believes they can help prevent further further degeneration, preserving as much function as possible.

"If we combine it with the macrophages treatment, we can hopefully achieve more than that," says Harel.

The company has just completed the technology transfer from the Weizmann Institute and is also looking at an opthalmic version. Glaucoma - the degeneration of the optic nerve - is a vast market for drug treatment. If Proneuron's therapy works it may be able to prevent degeneration of the optic nerve and, according to Belkin, will lead to the possibility of eye transplants - something that has been impossible before now.

Harel is now negotiating with several opthalmic companies but won't reveal more details.

The last project is a clinical drug therapy to enhance immune privilege. The company is trying to isolate and synthetically manufacture a natural steroid that will have less side effects than existing steroids. The potential for this drug is huge as steroids are used to treat a huge range of illnesses and diseases, but have quite unpleasant side effects. It has potential to treat pa-tients with diseases including Alzheimer's, Parkinson's and multiple sclerosis.

"This project is 1,000 times more valuable than the others, but it's so far away that I don't even know how to put it on the time scale. It's a question of time, money and luck," says Harel.

Proneuron is not alone in this field. Though it doesn't compete with the large pharmaceutical companies, there are at least five other small companies involved in a range of therapies.

"This is the holy grail of neuro-medicine but Proneuron is years ahead," says Belkin. "As far as we know no one has done clinical trials and no-one got the same results in rats."

The field of biotechnology is an extremely expensive one and it's hard to believe that Proneuron has advanced so far on just $7m. Harel says he keeps tight control over spending. The company, for instance, doesn't have a CEO. In addition Harel keeps Proneuron focused. "It wouldn't be a big deal for us to open up to 20 new projects but it's not our way; we focus on one project at a time."

To advance to the next stage, however, the company does need money and another private offering is now being organized. With this money Harel plans to set up cell centers in Belgium and the US and to take the clinical trials to the next stage.

If the first treatment proves a success in 2002, Proneuron will begin to see its first sales. Harel estimates that the company can expect to see penetration rate of about 20 percent in the first two years, that adds up to about 1,000 patients, all paying about $50,000 each. "It's enough," he says.

So far the company hasn't decided how to proceed. There's a chance it may license its therapy out to a larger company, or it may choose to go it alone. "First we have to prove the concept, then we'll talk," says Harel.

At the moment excitment at the company is running high. "This could be one of the greatest medical breakthroughs. The ramifications are phenomenal," says Belkin, who says he can even envisage carrying out the first ever eye transplant.

Harel is calmer. He knows the risks involved. At the moment the fact that the animal trials worked is enough. He does not, however, want to think about the possibility of the treatment not working. "We don't consider failure at the moment."