other organizations and companies, also University of Western Australia in Perth
contributed funding to the conference for development of exon skipping. The
itself. skipping is accomplished with
Among the presentations “antisense” compounds, which
were updates on: keep cells from obeying (mak-
n gene and cell transfer ing “sense” of) targeted genetic
strategies instructions.
n how muscle stem or pre-
cursor cells become mus-
_{cle cells} PTC124 Shows
n stop codon read-through, Benefit in Mice
a strategy in which cells
are coaxed to ignore ab- MDA grantee Lynn
normal stop signals in Megeney’s presenta-
the dystrophin gene ^{tion showed that}
muscle precursor cell
n stimulation of utrophin, _{maturation (differentia-}
a protein very similar to tion) seems to require
dystrophin that can at breakage of DNA
by Margaret Wahl least partially compensate ^{strands, which the cell}
_{for its absence} then has to repair.
The underlying cause of Duchenne n exon skipping, a technique
muscular dystrophy (DMD) can in which error-containing sections
be any of a large number of muta- of the dystrophin gene are masked,
tions in the gene for the dystrophin pro- allowing production of functional
tein. One strategy now being tested for dystrophin protein molecules.
overcoming this problem is gene ther- Gertjan van Ommen at Leiden
apy, the insertion of new dystro- University in the Neth-
phin genes. Another is the trans- erlands presented some
plantation of cells that give rise to exciting new data. He
muscle. Other strategies include announced that four
changing the way cells interpret DMD-affected boys in
the genetic information that’s the Netherlands who
already there; reducing some of were given an exon skip-
the secondary effects of dystro- pingcompoundtargeted
phin deficiency; and compensat- to their genetic errors all
ing for the loss of dystrophin. began producing what
appears to be functional
Gertjan van Ommen of ^dystrophin.
Leiden (Netherlands) Van Ommen, with
University presented new colleagues at Leiden
data showing that all four _{University and at}
boys who received an
exon skipping construct ^{Prosensa, a Dutch bio-}
More than 40 speakers and some began making dystro- tech company, gave each
150 registrants convened in phin in the injected leg of the 10-to-13-year-old
O t t a w a , O n - ^muscle. boys a single injection of
tario, May 3-5 an exon skipping com-
to celebrate the 20th pound into a front lower leg muscle. All
anniversary of the were missing sections of the dystrophin
identification of the gene lying between exons 48 and 52.
dystrophingeneand Twenty-eight days after injection,
protein. biopsies of the boys showed strong
Nearly all present- and even dystrophin distribution in the
ers and many of the injected area. There were no adverse
registrants were cur- effects except mild injection site pain.
MDA grantee Bernard rent or former MDA The Dutch group hopes to start sys-
Jasmin at the grantees, and many temic injections of the exon skipping
^{University of Ottawa} acknowledged MDA construct later this year.
^{presented data on} asthefundingsource For several years, MDA has sup-
stimulating utrophin
_{production to compen-} that allowed them ported Judith van Deutekom at Leiden
sate for dystrophin’s to start their careers. University and Stephen Wilton (see
absence. M D A , a l o n g w i t h “Team Finds 300,” page 16) at the

Tackling DMD
on Many
Fronts

20th Anniversary
of DMD Gene ID
Marked in Ottawa

Scientists say data from mice that received PTC124, an experimental drug already in clinical trials in boys with DMD, confirm the “proof of principle” on which the drug’s action is based.

The investigators, including

MDA grantee H. Lee Sweeney of the University of Pennsylvania, published their results online April 22 in the journal Nature.

PTC124, developed by PTC Therapeutics of South Plainfield, N.J., with funding from MDA, is a drug that causes cells to ignore stop codons that are abnormally (“prematurely”) placed in the dystrophin gene. About 15 percent of DMD-affected patients have stop codon mutations.

Dystrophin-deficient, DMD-affected mice with premature stop codons that received PTC124 by a combination of oral feeding and/or injections were stronger and showed less contraction-related muscle damage than is characteristic of these mice.

Blood levels of the enzyme creatine kinase, which leaks out of damaged muscle cells, dropped significantly compared to those of untreated mice, indicating many more muscle cells remained intact.

Tests showed the treated mice produced about 20 percent to 25 percent of the normal level of full-length dystrophin, which was in its normal place in the muscle fiber membrane.

In dystrophin-deficient mice, exercise normally leads to muscle fiber damage and loss of strength. However, that didn’t happen in the PTC124-treated mice.

“We could not detect the changes in force due to damage caused by exercise that we typically find in animals with this disease,” Sweeney said.

Of equal importance, the investigators found no evidence of “off-target”