GENE therapy has proved one of medical research’s greatest disappointments.
Not only has it failed to make many people better, it’s made a significant
number worse. And following the exposure of activities at the University of
Pennsylvania, we now know that unethical use of gene therapy has killed at least
one patient.
But researchers haven’t given up hope of finding ways to treat inherited
diseases. “We were frustrated that not much was happening, that it was
short-term, and that even if we succeeded we would not be able to reverse the
disease,” says Charles Coutelle, a leading researcher in gene therapy at
London’s Imperial College School of Medicine. So Coutelle, and a handful of
groups in the US, are pinning their hopes on using gene therapy to treat
someone before they’re born. This was a hot topic among delegates to the
Millennium Festival of Medicine in London last month.
Treating the baby in the womb has several advantages. First, because it’s
small there’s a better chance of getting the genes to all the cells that need to
be corrected. Going in early, before the immune system is fully developed, also
avoids an immune reaction to the products of the introduced genes, and the
systems that deliver them. And finally, in utero therapy for disorders such as
cystic fibrosis would prevent them causing lasting damage.
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Animal tests are already showing success. In a recent trial, Coutelle and his
colleagues used non-infective virus-like particles to carry the gene for the
human blood clotting agent factor IX into sheep embryos. The added genes produce
the protein for as long as they remain in the animals’ cells, but they are not
incorporated into the cells’ DNA. When the lambs were born, their levels of
human factor IX were 80 per cent of the normal human level—-which in
people would be enough to keep haemophilia at bay.
The lambs only made factor IX for around 40 days after birth, highlighting a
problem with any form of gene therapy that doesn’t integrate the introduced
genes into the patient’s own DNA. Eventually, Coutelle and his team are hoping
to find ways of doing this, allowing fetal gene therapy to introduce genes that
will remain active for life.
Coutelle says that his therapy could eventually be simple and safe enough to
treat genetic risk factors for even common conditions such as raised
cholesterol. “You could treat it with a single shot during pregnancy.” Already,
Janet Larson from the Ochsner Medical Foundation in New Orleans and her
colleagues have used gene therapy on unborn mice carrying the genes for cystic
fibrosis. The treatment completely and permanently prevented the disease
appearing in the animals.
It’s a rosy vision, but there’s a problem. The earlier you put genes into a
fetus or an embryo, the better the chances that they get where they are supposed
to go. But this also makes it more likely that the DNA will reach developing
eggs or sperm, introducing “germline” changes—genes that will be passed on
to future generations.
Because of this risk, gene therapy on fetuses is effectively banned in
Britain. “With in utero gene therapy, you are dealing with a much smaller
target,” says Norman Nevin, chair of the government’s Gene Therapy Advisory
Committee, which decided in 1998 that it would not approve any proposals for
this type of treatment. “At this point in time, if a proposal is submitted for
in utero gene therapy, it is unlikely to be approved, because of the risk of
accidentally introducing germline changes. We don’t know what the consequences
of that would be,” Nevin said.
According to Coutelle, this is unfair, as it applies more stringent standards
to gene therapy than to other treatments. “It is a well known fact that
medically we are creating mutations by chemotherapy,” he says. “No one seems to
worry about that.” Because the mutations are random, it is impossible to trace
any damage to the germline, he says. “We should try to avoid germline gene
transfer, but if it happens, it has to be balanced against the benefits. And
that holds for all gene therapy trials.”
According to Coutelle, his team could be ready for human clinical trials of
fetal gene therapy in four or five years’ time. But will they be allowed
permission? “When we are in a position to apply for it, then we’ll return to the
issue,” he says.
There is similar pressure to push forward fetal gene therapy in the US too.
In 1998, French Anderson, director of the gene therapy laboratories at the
University of Southern California, submitted two proposals to the National
Institutes of 91ɫƬ for carrying out gene transfer into human fetuses which
would have a “distinct possibility” of leading to germline changes. He submitted
the proposals with the aim of stimulating debate in the area. But soon the
question could be of more than academic interest. Anderson says that after more
than a decade of research on fetal gene therapy in animals, he could be ready
for human trials in as little as three years.
Other researchers think the regulators are right to be cautious. Cell
biologist Stuart Newman from New York Medical College agrees. “Somatic
modification in embryos is a grey area because there is a greater likelihood of
germline modification. If it is ever going to be done, it has to be done right.
We would have to be assured that there was a vanishingly small chance of
affecting the germline.”
“My concern is that we don’t know what we’re doing,” says John Bell, head of
clinical medicine at Oxford University. “Maybe it will be acceptable in a
thousand years’ time, but not today.”
A report by the American Association for the Advancement of Science entitled
Human Inheritable Genetic Modifications, published in September,
concludes that it is “very likely” that some of the adult gene therapy trials
authorised in the US have had unintentional impacts on the germline. It adds
that the possibility of genetic problems occurring because of these germline
side effects seem “at least as great or greater” than problems that might arise
from altering the germline intentionally.
With such unintentional changes already taking place, some feel that it is
only a matter of time before in utero gene therapy is endorsed, and perhaps
germline gene therapy too. In fact, Newman suspects that some people may be
deliberately downplaying concerns about in utero gene therapy in order to soften
up public opinion and pave the way for germline therapy.
Most researchers, however, think deliberate germline modification is some way
off, not least because its medical uses are limited. For carriers of recessive
disorders such as cystic fibrosis, for example, IVF procedures would be needed
to correct an embryo’s DNA. And if you’re going to perform IVF, then other
techniques such as prenatal genetic diagnosis (PGD) could be used to select
embryos for implantation that did not have CF.
While the AAAS concludes that germ-line therapy cannot yet be carried out
safely in people, it looks ahead to the day when it might be used. The report
suggests, though, that the first use of the technique will not be aimed at
introducing genes that will be passed down the generations, but will simply be
to correct motility defects in sperm.
And while the debate over in vitro gene therapy rages, other developments are
causing consternation. Babies are already being made in the US with mitochondria
from a donor, meaning that they have DNA from three different individuals. “It
is starting to blur the question, `who are the parents of the child?'” says
Newman. “Society has not worked out what the implications of children having
three, four or ten parents might be. It’s a whole mess.”
The regulators argue that the risks of modifying the DNA our grandchildren
will inherit are too great for fetal gene therapy to be allowed. But Coutelle
sees another point of view. The technique, he says, could enable us to cure many
inherited diseases before birth. And that, he says, must make it worth pursuing.