October 21, 2004.
By Roger Highfield,
The human brain is the most complex known object in the universe. Even though scientists still understand little about how the 100,000 million nerve cells in this chemical machine store memories and create consciousness, they are racing to develop ways to repair the brain as it ages and after it is damaged by strokes and diseases such as Parkinson's.
Helping hand: a vial containing brain stem cells produced by ReNeuron's cloning technique
In the past few weeks, two British companies have announced promising new approaches: one is growing replacement nerve cells and the second is using viruses to carry out delicate brain surgery at the molecular level.
In Guildford, Dr John Sinden's company, ReNeuron, has found a way to mass produce - clone - human foetal nerve stem cells in the laboratory. The result is a potentially unlimited supply of human nerve stem cells for repair.
Previously, scientists have tried to treat Parkinson's with foetal brain tissue. But this required several foetuses for each patient, which raised practical and ethical concerns, and there was poor control over what tissue was being implanted. One company, Layton Biosciences in America, used nerve cells isolated from a special cancer, called a teratocarcinoma. But there is unease about implanting cancer cells.
Instead, ReNeuron took a few thousand brain cells from a tiny sample of brain material from a single foetus aborted for medical reasons - with ethical approval, consent of the mother and no inducement - and found a way to derive around 100 cell lines, from which a handful of promising lines was chosen.
The tricky part was finding out how to multiply the cells into vast quantities, so freeing the scientists from the need to use any more foetal material, said ReNeuron's Dr Kenny Pollock. The team eventually found that a virus could be used to introduce a growth-promoting gene, called c-mycER, which enables the foetal brain cells to divide endlessly. Using this approach, a single cell can generate a billion identical cells. The clever part was that, for the gene to work, a drug called 4OHT also had to be added. And when 4OHT was withdrawn, the cells stopped dividing.
By using genetic surgery to temporarily "immortalise" cells, the company has banked millions of nerve stem cells in its laboratories. One such cell line, called ReN001, was tested in rats and reliably turns into functional nerve cells or neurones.
"They have the world's first ever clonal immortalised stem cells which are 100 per cent stable, and are homogeneous and fully functional," said Sir Chris Evans, chairman of Merlin Biosciences, which has helped fund the work since it was started by Dr Sinden at King's College London a decade ago.
Stem cells, as the name suggests, are parent cells of other types. The hope is that when ReNeuron's nerve stem cells are implanted, naturally present growth factors will turn them into various types, be it brain cells to treat stroke and Huntington's, nerve cells to repair a damaged spine, or retinal cells for blindness.
Earlier this month, encouraging studies of the use of the human stem cells to treat stroke in rats were reported to the American Neurological Association annual meeting in Toronto by Dr Sinden. The cells, though human, caused a minimal inflammatory response and treated rodents had a "significant" restoration of movement and an enhanced sense of feeling, in detecting and removing sticky tape on their paws. Later this month, at the Society for Neuroscience meeting in San Diego, the company will also publish encouraging results in treating animal models of the brain disorder Huntington's disease.
After further safety checks in animals, ReNeuron hopes to have approval to begin clinical trials by the start of 2006, initially in around 30 patients who have suffered long-term disabilities after stroke. If injections improve sensation and function, ReNeuron believes its ReN001 could be the first neural stem cells to treat a major disease.
Meanwhile, the use of viruses to modify brain cells is being developed by Professor Alan Kingsman of Oxford Biomedica. For two decades, he and his wife, Sue, have studied a family of viruses, including HIV, called lentiviruses. From one, the equine infectious anaemia virus, they have perfected a way to carry out genetic surgery. Crucially, while most viruses invade dividing cells, these lentiviruses offer a way to deliver genes to non-dividing cells such as neurones, the major functional cells of the brain.
The Kingsmans dismantled these viruses: some genes (called gag/pol) make the core, which determines the ability of the virus to invade non-dividing cells; others code for the envelope, which makes a halo of "spikes" that enable the virus to stick to cells; and there are genes that regulate how a host cell is turned into a virus factory.
Inessential bits are stripped from the natural virus and replaced by genes that treat disease. The result: modified viruses that are unable to cause infection but can deliver a therapeutic gene or genes to the patient.
The resulting "lentivectors" blend genes according to the task. One mission is to repair the damage caused by Parkinson's disease, when 200,000 cells in a part of the brain called the substantia nigra no longer make dopamine, a messenger chemical. An inability to move and tremors develop because dopamine is needed by another region of the brain, the striatum. Now the team has developed a virus to implant three dopamine-making genes into this region and not into others, since this could cause side effects.
Experiments on rats show how the genes can be delivered precisely by injections of a millionth of a litre of virus. "What we find is that, with the right volume of material going in at the right pressure, we can control the distribution of the genetic modification in the brain," said Prof Kingsman.
An animal model of the disease has shown that injections of this lentivector, "ProSavin", produce remarkable improvements. Injections can restore almost normal movement. "The ProSavin animals are up and jumping about and look completely normal," said Prof Kingsman. The company hopes to apply to use the approach, which would require injections directly into the brain, next year.
In other research, the Oxford BioMedica team has coated a lentivector with the proteins from a rabies virus. This has enabled the team to exploit a remarkable property of this virus: once introduced into muscle by a bite, the natural virus can infect motor neurones, the nerve cells in the spine that have extensions - called axonal projections - that project up to a metre to transmit brain signals to muscles.
Rabies-coat proteins enable the engineered lentivector to hitch a lift on molecular motors that travel up and down the neurones so it can dump its therapeutic genes into the heart of the motor neurone. Aside from being a "fascinating research tool", this virus offers a way to treat motor neurone disease.
One form of the disease, called ALS, usually results in paralysis and death three to five years after onset. There is currently no known cure for the disease, which affects about 100,000 people in Europe and America.
In Oxford Biomedica's treatment, a lentivector is injected into muscle to deliver the gene for VEGF, a nerve-protecting factor, into the nerve cells of the spine. A single jab delayed onset and slowed progression in mice, extending life expectancy by 30 per cent, according to a recent study in the journal Nature by Dr Mimoun Azzouz of Oxford BioMedica and the Centre for Transgene Technology and Gene Therapy, Belgium.
Human trials are now planned in 2006, bringing hope to the 5,000 or so sufferers in Britain. The downside is that, to get the virus in all the motor neurones, patients would be turned into pincushions. But, given that it is such an awful disease, Prof Kingsman expects patients to have few qualms. "This is amazing technology," he said.
End of article.
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