FROM: THE DAILY TELEGRAPH(LONDON)
October 20, 2004, Wednesday
Features Pg. 16

HEADLINE: Could this fix a damaged brain? Cloned nerve stem cells and the
use of
viruses as micro-surgeons could soon help people with serious illnesses.
 Science Editor Roger Highfield reports
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.

   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withdrawn, the cells stopped dividing.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."

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