A new gene
therapy strategy has shown early promise in tests on mice with the most
severe form of the muscle-wasting condition congenital muscular dystrophy,
Swiss researchers reported.
The technique
restored the rodents' muscle function, suggesting drugs based on a similar
approach might alleviate symptoms of the disease in humans, they said in
the British journal Nature.
In the experiment,
genetically altered mice lacked the laminin-2 protein, the absence or mutation
of which leads to muscle degeneration. The researchers replaced the missing
molecule with a specially created miniature form of another muscle protein,
called agrin.
This replacement
therapy allowed muscles to work properly in the mice.
The study opens
the door to potential treatments for muscular dystrophy, though these are
still years away, researchers told United Press International.
In addition,
the findings demonstrate how small versions of large proteins could be
useful for gene therapy in general, especially as they are less likely
to cause immunological responses, said lead author Markus Ruegg of the
University of Basel in Switzerland.
"It's very exciting
to have identified yet another protein that could serve as a therapeutic
target to reverse the muscle weakness and wasting in a form of muscular
dystrophy," said Sharon Hesterlee, director of research development at
the Muscular Dystrophy Association in Tucson, Ariz.
"The fact that
agrin can stand in for the loss of the laminin protein could be important
for developing a gene therapy approach, as the body is unlikely to reject
agrin as foreign-whereas laminin might be seen as foreign because these
children may not be making any laminin at all," she told UPI.
"Also, this
group has managed to make a 'mini' version of agrin, giving us more versatility
in our choice of gene therapy vectors," or delivery vehicles.
The findings
"open up the field to different strategies, increasing the chances of success
of developing therapies," said Kay Davies, Dr. Lee's professor of anatomy
in the Department of Human Anatomy and Genetics at Oxford University in
England.
The work builds
upon Davies' earlier studies that pointed to the potential promise of this
approach. Davies was not involved in the current research.
"Our work provides
strong evidence that replacement therapies can successfully be used to
treat a disease whose molecular cause is known," Ruegg told UPI.
Such a strategy
was used successfully by Davies and colleagues in mouse experiments that
showed symptoms can be minimized by replacing dystrophin, which is missing
or mutated in two common types of muscular dystrophy, with the protein
utrophin, which corresponds in structure and origin.
"Our work shows
now in one case that this can be achieved with proteins that are not homologues
but share 'only' functional properties," Ruegg told UPI. "We believe that
in this general sense, our findings are not restricted to congenital muscular
dystrophies or muscular dystrophies in general. Such a replacement therapy,
if proven that it works, would also be applicable to humans."
"This is a
significant study because it demonstrates that rational protein design
can be used to develop therapeutic tools," Davies told UPI. "Investigators
have replaced the function of one protein with another in the past, e.g.
utrophin for dystrophin, but no one has tailor-made a protein to do a particular
job."
Questions remain,
such as how much agrin is needed for the rescue and whether the full-length
agrin also restore muscle function.
"Both questions
are being investigated in my laboratory," Ruegg said. "It is too early
to say whether they would provide a cure." Gene therapy in general still
faces many obstacles, the researchers cautioned. These include: overcoming
rejection by the body's immune system, controlling production of genes
that would specifically target the appropriate tissue, ensuring the proper
spread of the therapy, developing efficient and accurate modes of gene
delivery, Ruegg said.
In this case,
the problems of delivery and adverse immune reaction appear to be solved
with the use of the miniaturized agrin, said Ruegg, who manages the start-up
company MyoContract Pharmaceuticals Research Ltd. The company is developing
drug treatments for neuromuscular diseases such as Duchenne muscular dystrophy.
Patients with
the severe form of dystrophy also suffer from symptoms originating in the
nervous system, so restoring muscle function-assuming it could be done
with drugs that increase agrin levels-would only be of partial help, Ruegg
said.
"The success
of the concept must be shown for other cases," he said. "Clinical applications
are certainly many years down the road."
Congenital muscular
dystrophy, a rare disorder that strikes both genders equally at or soon
after birth, can have several causes, including genetic mutations. Children
with the disease suffer muscle degeneration that prevents them from walking
or even standing up and they often die prematurely due to respiratory complications.
There is no cure or treatment for the disease.
"I think that
therapy for muscular dystrophy is getting closer," Davies concluded. "This
result demonstrates clearly that basic studies of muscle function and analysis
of muscle proteins in different disease states is really yielding results
now which will lead to novel therapeutic approaches."
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