Scientists have used gene therapy to halt the
progression of adrenoleukodystrophy, a fatal neurodegenerative disease caused by
a single defective gene, in two seven-year-old boys.
It took more than a decade to refine the therapy, in which stem cells taken from
the boys’ bone marrow were hacked with healthy copies of the gene, then returned
to their bodies. Without them, the boys would soon be dead.
"They would now be unable to speak, to walk, to communicate, to sit, to eat.
They would be in an advanced stage of the disease, in a vegetative state," said
Patrick Aubourg, a pediatric neurologist at France’s National Institute for
Health and Medical Research who led the treatment’s development. "Instead they
go to school. They live a normal life."
The gene at the root of adrenoleukodystropy — ALD for short — is called ABCD1,
and produces a protein necessary to maintain myelin, a compound that acts as an
insulator for nerve fibers in the brain and peripheral nervous system. As myelin
degrades, the fibers cannot conduct electrical impulses.
The boys who received the treatment suffered from the early form of ALD, in
which the defective gene is found only on the X chromosome. Technically known as
X-linked ALD, it affects boys, typically starting in childhood and killing them
in two to three years. It can be treated with bone marrow transplants, but
success rates are low, and toxic immune system-suppressing drugs are needed to
prevent patients’ bodies from rejecting foreign tissue — if, that is, a donor
can even be found.
No such donor was found for the children, who
had just a six-month window after diagnosis in which treatment could be started.
After that, it would have been too late. So their parents turned to Aubourg’s
therapy, which had only been tried in laboratory animals.
One of the children — their identities remain confidential — received the
treatment two and a half years ago. The other received it three years ago. Their
story is described in a paper published Thursday in Science. In both, the
disease has stopped progressing. Their brain scans show myelin damage that has
stopped, and their new genes are active as ever.
The results are as striking as any previously delivered by gene therapy, a
biotechnological technique that after nearly two decades of anticipation has
largely failed to deliver on its lab-bench promise — though that may be
changing.
"There is reason to think that this will last for the rest of their lives," said
gene therapist Nathalie Cartier of NIHMR, the study’s lead author.
In 1993, when Aubourg discovered how to duplicate the ABCD1 gene in a
laboratory, he envisioned adding it to blood stem cells, which give rise to the
different types of blood cells — including, critically, the cells that make
myelin. Every new cell would produce the correct protein. The ALD would
disappear.
This type of approach is one example of gene therapy, a technique that even now
is highly experimental, and was more experimental then. The first "vector" used
by Aubourg — a virus engineered to carry new genes into target cells — succeeded
in delivering its payload just .001 percent of the time. Even this miniscule
success rate was enough to improve symptoms in mouse models of ALD, but he
didn’t trust it to work in people.
Aubourg went back to the drawing board. He used a new vector made from a human
immunodeficiency virus from which the genome had been removed, leaving only
HIV’s cell-penetrating shell. Inside this he put the new ABCD1 gene, and a
string of DNA that helps it fuse with target chromosomes.
The new vector, called a lentivirus, didn’t work all the time, but it was far
more efficient than the old one. In the two boys who received the treatment, 15
percent of the stem cells in their bone marrow now possess a copy of the healthy
ABCD1 gene. These cells are essentially immortal, and should provide a steady
supply of healthy myelin-producing cells in perpetuity.
"Even this low-end number is high enough," said Aurora Pujol, an ALD researcher
at Spain’s IDIBELL Research Institute. She knew the two boys when they were
patients at a hospital in Spain, waiting in vain for bone marrow transplants,
and connected them to Aubourg’s laboratory. "They did a great job."
The boys did not escape unscathed, and still suffer from some cognitive
difficulties. And though no side effects have been observed, far more testing is
needed to be certain that the treatment is safe. "The risk is never zero," said
Auborg.
Indeed, gene therapy is still best-known for its high-profile failures. In 1999,
18-year-old Jesse Gelsinger died during tests of a gene therapy for a rare
metabolic disorder. In 2003, two French children receiving treatment for severe
immune deficiencies developed leukemia.
But with the recent success of a gene therapy for blindness, and the refinement
of new, apparently more reliable methods, gene therapy may have turned a corner.
"This is an important step forward for ALD, but not only for ALD," said Pujol.
"The lentiviral vector approach can be applied to other single-gene diseases."
Jeffrey Rothstein, a Johns Hopkins gene therapist who specializes in Lou
Gehrig’s disease, warned against extrapolating too much from the early ALD
results. "It’s great that it worked, but that doesn’t guarantee success in other
diseases," he said.
But University of Pennsylvania bioethicist Art Caplan, who has followed gene
therapy since its beginning, shared some of Pujol’s excitement.
"I think this is the beginning of a turnaround," he said. "It took a long time
to move from animal research to clinical success. It took more than a decade to
get anywhere. But these breakthroughs show that this long-touted technology is
about to produce clinical benefits."
