Two
children with a common neurodegenerative disease are seeing
early signs of success from a pioneering gene-therapy treatment,
researchers report this week.
The results
raise hopes for a treatment for adrenoleukodystrophy (ALD), and,
the researchers add, mark the first successful use of an
attenuated HIV virus to carry a therapeutic gene into a
patient’s cells.
HIV is a
promising vector for transferring corrective genes into a host —
it can penetrate directly into cell nuclei, making it a
theoretically efficient way to introduce new genetic material.
But until now it hadn’t been proven in a clinical setting. This
early success potentially opens the door to better treatments
for many other diseases involving the bone marrow and blood
cells, such as leukaemia, thalassemia and sickle-cell disease,
the researchers say.
The results,
from two 7-year-old Spanish children with ALD, were announced on
Sunday 28 October at the fifteenth Congress of the European
Society of Gene and Cell Therapy in Rotterdam, the Netherlands
ALD is caused
by a mutation on the X chromosome. This mutation causes
degradation of the insulating sheaths that surround neurons and
allow them to signal properly. The condition was made famous by
Lorenzo's Oil , the Hollywood film
outlining one family’s fight to help their son. The most severe,
cerebral form of ALD affects one in 17,000 people, with
two-thirds of sufferers being children. It progresses slowly at
first, but if no bone-marrow transplant is available it can
quickly progress to cause brain damage and death.
At present,
treatment is limited to giving preventative dietary supplements
and therapeutic bone-marrow transplants, with the attendant
shortages of donor tissue.
Word of
caution
Patrick
Aubourg and Natalie Cartier, researchers at Inserm (France's
national biomedical agency) who were working at the Saint
Vincent de Paul Hospital in Paris, attempted to fix the
X-chromosome defect using gene therapy. Working in collaboration
with the Californian biotech company Cell Genesys, they first
cultured the children's bone-marrow progenitor cells — which
give rise to all blood cell types — and transferred the
corrective gene to them using the HIV virus.
They then
destroyed the children's existing bone marrow using
chemotherapy, and reintroduced the modified cells, which took
hold within a month to produce new bone marrow and blood cells.
Samples taken showed that half of the new cells contained the
introduced gene, and that 20-30% expressed the corrective
protein. Such expression levels in gene therapy are
"exceptional" says Aubourg. The levels have remained stable for
more than two months in the children, despite the fact that the
cells involved are replenished every 24 hours.
Aubourg is
keen to emphasize that although the initial results are
encouraging, caution is warranted. The children will need to be
closely monitored to check the safety of the procedure, with the
main risk being that they might develop leukaemia as a result of
the risk of mutagenesis during gene transfer. Many previous
gene-therapy trials have failed because of serious problems with
side effects.
It will
also take another 18 months of follow-up before the team can
be reasonably sure that their gene transfer remains stable,
and that the level of corrective protein expressed is
sufficient to prevent clinical symptoms from developing, he
says. Both children are so far doing as well as would be
expected following conventional bone-marrow transplants, he
adds.
Aubourg
announced the findings before publication because of the field's
intense interest in using attenuated HIV vectors in gene therapy
for other diseases. Given the higher efficiency of such vectors,
demonstrating their feasibility would mark a "breakthrough in
gene therapy", he says.
Quickly
informing the field was a viable idea, says Laurence
Tiennot-Herment, president of the French Muscular Dystrophy
Association, which has funded Aubourg's work for a decade. "But
we must wait and see, as there is no publication yet, and there
are safety and other issues to consider," she adds. "I'm very
cautious for the present, but it's an important step."
