Å®ÉúСÊÓƵ

Gene therapy has cured mice of a muscle-wasting disorder similar to
Duchenne muscular dystrophy, a fatal disease that kills boys in their teens
or early twenties. The research shows that replacing a single gene can prevent
the destruction of muscle. But geneticists have questioned the relevance
of the work for treating humans because it does not tackle the crucial question
of how to insert the gene into every muscle.

Duchenne muscular dystrophy is one of the most common and severe disorders
to be caused by a single defective gene. The disease, which is inherited
on the X chromosome, affects around one in 3000 boys. Sufferers fail to
make dystrophin, a protein essential for maintaining the structure and strength
of muscle cells. Researchers hope that restoring production of the protein
will stop the relentless progress of the disease.

But DMD is a more difficult candidate for gene therapy than many other
inherited diseases because dystrophin, and its gene, are too large to ‘fit’
into the viruses normally used to shuttle genes into cells. To overcome
this problem, a team led by Jeffrey Chamberlain of the University of Michigan
Medical School created an artificial gene which is 200 times smaller than
normal. The researchers were able to leave out vast sections of ‘excess’
DNA that are found in the normal gene but are not essential for the production
of dystrophin.

Chamberlain’s group injected the artificial gene into the fertilised
eggs of ‘mdx’ mice, which develop a disease similar to DMD. Mice born from
these embryos generated 50 times the normal level of dystrophin in their
muscles and suffered no loss of strength (Nature, 19 August). ‘The research
tells us that we can put together a miniature version of this gene that
restores function,’ says Chamberlain.

Helen Blau, a molecular biologist at Stanford University in California
says restoring force and power is of ‘particular interest’, because so many
DMD patients die when the muscle in their diaphragms becomes so weak they
can no longer breathe.

Kay Davies, who is director of research at the Medical Research Council’s
Clinical Research Centre in London, says the important finding is that dystrophin
does not appear to be toxic when 50 times the normal amount is present.
This is encouraging because geneticists cannot regulate precisely how much
protein is produced by the body after gene therapy.

But both scientists question whether a miniature dystrophin gene is
the best approach to treating DMD. ‘In the context of gene therapy, it does
not advance us very much,’ says Davies. At last week’s international genetics
conference in Birmingham, Davies said the big problem is how to deliver
the gene to every muscle in the body.

Chamberlain’s technique of injecting the gene into fertilised eggs could
not be used on humans, not least because the added DNA would find its way
into the eggs and sperm of treated people. Such ‘germ line’ therapy has
been ruled unethical by the government’s Clothier committee on the ethics
of gene therapy.

Å®ÉúСÊÓƵs use viruses to carry healthy genes into the cells of affected
people. But Chamberlain’s miniature gene is still larger than many other
genes and, says Blau, it is too big to be carried by any of the well-known
viruses. Chamberlain is not convinced by this reasoning. ‘I think there
is a lot of potential,’ he says. He is looking at adenoviruses (which cause
cold-like symptoms) as a means of introducing the gene into humans.

Davies believes a radically different approach may offer the best hope
for treating DMD. Her research has focused on utrophin, a protein smaller
than dystrophin but with a similar overall structure. In embryos, utrophin
is found at the same position in muscle cells that dystrophin occupies
in later life. But before the child is born, utrophin is dislodged by
dystrophin. ‘It’s hopeful that we might in future . . . think about these
as interchangeable molecules,’ she says.

Davies aims to find the genetic switch that ‘turns on’ the utrophin
gene in embryos. If a drug can be identified that will turn this switch
on, then utrophin could be made to substitute for dystrophin. This work
is still at an early stage but, says Davies, ‘the possibilities of replacing
the gene in every muscle cell are so daunting that it’s worth trying other
approaches as well’.