The CNS is separated from the PNS and has immune privilege, 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 inflammation brings with it macrophages, a type of white blood cell that is vital for healing wounds and regenerating tissues. In the PNS, which does not have immune privilege, the nerves have the capability to regrow and become functional again. In the CNS, there's no inflammation, very few macrophages, and no regeneration. If someone suffers a spinal injury, or surgery on a brain tumor goes wrong, the body remains damaged for life.
Proneuron tries to induce CNS regeneration by taking active macrophages from a patient's PNS and injecting them into his spinal cord to cause a healing inflammation. Research on rats showed that those who received cell therapy after a spinal injury had left them paralyzed in the back legs and tail, could, within two weeks of the injury, regain some kind of mobility. Both the tail and the back legs regained about 50 percent of movement and coordination and the animal could partly support itself on its back legs.
By using the body's own cells, patients suffer less side effects than with drugs since they are part of the body's natural defense system. Cells can also be positioned exactly where they are needed in the body, unlike drugs which flood the whole body with chemicals.
"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," says Adrian Harel, the company's manager. "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 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."
The only drawback to this treatment, which has already received FDA approval, is that it must be carried out within the first two weeks after an injury. After this the window of opportunity closes. For existing paraplegics this treatment offers no relief whatsoever.
It is mostly this time limitation that makes it so difficult for Proneuron to find suitable patients for its clinical trials. "It's very hard to get patients within 14 days of an injury," admits Fulga. "They need to find out about us in a very short period of time and at the moment we still have very strict inclusion criteria." Another difficulty is that the patients must come to Israel where treatment is carried out at Tel Hashomer and Beilinson hospitals. Proneuron pays for all transportation and treatment costs. Once the current clinical trial is completed, another broader pivotal trial with some 30 to 50 patients will take place in hospitals across Europe and America. This is likely to be a much quicker process and if all goes well, the treatment could be on the market in two to three years.
The 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, and less than half of these are candidates for the therapy. For these few, however, the advantages are enormous. After injury to the CNS, most patients spend the rest of their lives in a wheelchair. Their life expectancy is 27 years and the cost of looking after them is huge. Proneuron's treatment costs about $50,000, and even if it only restores some feeling to the body, can help reduce long-term costs dramatically, aside from the clear improvements to a patient's quality of life.
Consider the actor Christopher Reeve, for example. He lost all movement below his neck after a riding accident. If Proneuron's treatment could have saved him just the misery of being on a respirator it would have improved the quality of his life enormously.
Considering the potential of this development Proneuron has managed to achieve a great deal with very few resources. The company employs just 30 people and so far has received only $13 million in cash.
Seed capital of $3.5m. came from the Hudson Investment Group in Los Angeles, which still holds the majority of shares. A further $3.5m. investment was made in July 1998. The investors in the second round were venture capital funds Nessuah Zannex, Lapid Medical Ventures, Pitango and Infinity.
In 2000, investors pumped in a further $6m. in two rounds of fundraising in February and December last year. At the last placement the company was valued at $30m. and Amir Galor, general manager of Israel Infinity Fund told Israel's business newspaper, Globes: "Infinity believes that Proneuron's technology is about to constitute one of the world's greatest breakthroughs."
The reason why Proneuron can do so much with so little is because of the nature of the treatment. Normally drug development can take 12 to 17 years and cost between $400m. to $600m. Because Proneuron's therapy is harnessing the body's own cells, clinical trials are far smaller and Proneuron only has to prove that its treatment works on a few dozen patients rather than hundreds as in the case of drug therapy.
Proneuron is also working on two other therapies. The first is neuroprotection, a treatment based on activated T-cells (another form of white blood cell) that help protect non-injured neuron 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, Proneuron believes it can help prevent further degeneration, preserving as much function as possible.
This treatment can also be used for almost any disorder of the CNS. This includes Alzheimer's and Parkinson's disease.
The company is also looking at an ophthalmic 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 lead to the possibility of eye transplants - something that has been impossible before now. Proneuron has started initial trials of this therapy and is applying for FDA approval. Once this has been received clinical trials can go ahead, possibly in the next year.
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 patients with diseases including strokes, Alzheimer's, Parkinson's and multiple sclerosis.
This has the potential to be an extremely lucrative drug, but it is still at a very early stage of development.
It is good, however, to have projects like this waiting in the wings. "If we are only successful in one project it will be good enough to keep the company working forever," says Fulga.
Though these two therapies are exciting, Proneuron's major goal right now is to get its first project out on the market. Once all clinical trials are completed, the company aims to set up Proneuron cell centers where patients can receive immediate treatment, next to spinal cord injury centers all over the world. In the US, alone, there are 16 spinal cord injury centers.
Fulga envisions a time when there are one or two cell centers in most countries around the world.
The most obvious question is who will pay for these treatments. Fulge believes that insurance companies are most likely to bear the brunt of the cost, though patients may also pay for any opportunity to improve their quality of life. "If we can prove this is an effective treatment then it will be much easier to get reimbursement from insurance companies," says Fulga. "These patients are expensive to maintain in medical and social terms, and their quality of life can be improved ramatically with our help."
Though Fulga maintains that Proneuron does not face any real competition, he admits that there are other companies such as Californian company NeoTherapeutics now running clinical trials for its drug Neotrofin. The drug has been shown to increase cell growth in Alzheimer's patients.
Elsewhere, researchers at Indiana University and Purdue University have teamed up to study the effects of electrical fields on spinal injuries. The study began in November and three people have taken part so far.
If these treatments are successful and reach the market first, Proneuron may find it much harder to market its own therapies.
Fulge, however, says he is not unduly worried. "It doesn't matter if they finalize their studies before we do. Our approach is so different from any other that even if someone else has a good therapy it will probably be synergistic to ours, not mutually exclusive."
Competition or not, Proneuron has a great deal of work ahead. Up to now it has worked primarily as an R&D outfit, but in the coming years it must change to incorporate a heavy sales and marketing slant. The company must also begin transferring its operations to the US. The company was actually registered in Delaware in the US, though the office there has remained only a virtual one up to now. Once the company starts to hold clinical trials around the world - an expensive business in itself - the US office will take on increasing importance.
To carry out these changes, Proneuron needs money, and in much larger sums than before. Fulga is aware of this and says the company is already exploring different avenues including a private offering, which could take place in the next few months. Fulga doesn't dismiss the chance of a public offering if market conditions ripen, however. Biotech, afterall, has been far less damaged by the current crisis than the rest of the high-tech
industry.
And the future? "You have to dream in order to answer that question," says Fulga. "I hope that Proneuron will be a successful biotech company focused on neurological disorders and also developing treatments for pharmaceutical disorders. There are so many injuries and diseases that we will be able to treat that are today untreatable." Once clinical trials of the spinal cord cell therapy are completed, Proneuron will begin to see its first sales. Company estimates suggest that it can expect to see a penetration rate of about 20% in the first two years, which adds up to about 1,000 patients. The main task now is to complete the clinical trials.
"What we need now is patience and patients," said Fulga. "We really want to know if our therapy is effective and need the help of patients to find this out."