Some areas in which research is being focused at the moment include:
This approach aims to skip the faulty section of the gene so
that dystrophin protein can be produced, albeit in a shortened form. It
is hoped that this will drastically reduce the symptoms of DMD to a
severity similar to that experienced by people with Becker muscular
Exon skipping drugs are sometimes called
‘molecular patches’ or referred to by their technical name ‘antisense
oligonucleotides’ or ‘AONs’. Molecular patches are not universally
applicable to all boys with DMD because they must be specific for a
patient’s particular genetic error. The dystrophin gene is made up of 79
pieces called exons, and mistakes that cause DMD can occur in any of
these. Initially molecular patches are being developed that work on the
parts of the gene that most often contain mutations. If these prove to
be successful more exon skipping drugs will be made to target other
regions of the dystrophin gene. In total it is thought that
approximately 83 percent of boys with DMD may be able to be treated by
exon skipping but this will require the development of more than 100
different molecular patches which could take some time.
Two similar exon skipping technologies
are currently being tested in clinical trial – by the companies Sarepta
Therapeutics and Prosensa (in collaboration with GSK). Their molecular
patches have been given the names ‘eteplirsen’ and ‘drisapersen’
respectively and they are both designed to skip exon 51 of the
dystrophin gene which could help about 13 percent of boys with DMD.
Results from the phase 2 trials of
eteplirsen (Sarepta) are looking promising with dystrophin produced in
the muscles and walking ability stabilised. The results should be viewed
with caution though because testing has so far only occurred in a small
number of patients. A phase 3 trial is now being planned.
Unfortunately a large phase 3 clinical
trial of drisapersen by GSK did not prove drisapersen to be effective.
This was announced in a press release on 20 September 2013. The trial
tested drisapersen in 186 boys from 20 countries around the world (not
Australia) for 48 weeks. Preliminary results showed that the treated
boys performed no better at muscle strength tests (including the six
minute walk test) than those receiving placebo. However the drug's
original developer - Prosensa - has revealed that, based on more
clinical trial results, it may work if boys are treated younger and for
In March 2014 Prosensa released news from
a smaller phase 2 trial of drisapersen which tested two different doses
of the drug in 51 biys with Duchenne MD. The phase 2 trial showed that
boys who received the higher dose of drisapersen (the same dose as in
the phase 3 trial) experienced stabilisation and even some improvement
in their muscle function as measured by the six-minute walk test after
24 weeks. They maintained this stabilisation for another 24 weeks after
treatment was stopped. However, the number of boys treated was small and
the results were not statistically significant. Therefore, further
analysis of the results in combination with the results of the other
clinical trials of drisapersen will be required.
The boys in the phase 2 trial were on
average younger than those in the phase 3 trial and Prosensa is
speculating that this is the reason for the conflicting results. It is
not known whether boys need to be younger for the treatment to work or
if the way treatment success was measured - the six minute walk test -
is only reliable in younger boys.
The aim of gene therapy for DMD is to introduce a healthy
synthetic copy of the dystrophin gene into the muscles so that
dystrophin protein can be made. Several challenges exist with this
Firstly, the dystrophin gene is too
large to fit inside the virus used to deliver it to the muscles. To
address this, scientists have produced a shortened version of the gene
by removing non-essential parts. This shortened gene is called
mini-dystrophin and it is similar to the gene that some mildly affected
men with Becker MD have.
Secondly, the body may recognise the
virus or the newly synthesised dystrophin protein as foreign and mount
an immune response against it which would drastically reduce the
effectiveness of the therapy. Indeed this is what happened in a small
clinical trial testing mini-dystrophin gene therapy in boys with DMD.
Research is ongoing to understand this immune response and find ways to
avoid it before another clinical trial is started. Drugs that suppress
the immune system may need to be given and it is also thought that the
way the gene therapy is designed and administered may help to avoid an
In research published in October 2013 it
was shown that it may be possible to use a technique called
plasmapheresis to prevent an immune reaction during gene therapy.
Plasmapheresis, which is widely used to treat patients with autoimmune
disorders, involves filtering antibodies out of the blood. The antibody
loss is temporary; the body begins producing new antibodies within a few
hours of the procedure.
Reading through stop signals
Ataluren (previously called PTC124) is an oral drug that
targets a specific type of mistake in the genetic code, called a
‘nonsense mutation’, which affects approximately 10 to 15 percent of
boys with DMD. This is when a stop signal is present part way through
the gene. Ataluren encourages the cell to ignore this stop signal and
continue to read the full set of instructions contained within the gene.
Ataluren has been tested for DMD in a phase 2b clinical trial which
showed that it may be able to slow down the rate of decline in walking
ability. A larger phase 3 trial is underway to confirm these results
prior to applying for the drug to be approved for sale. Researchers are
also investigating alternative drugs to ataluren that may be more
effective at reading through stop signals, but these are not yet ready
to be tested in clinical trial.
Stem cell therapy
In this procedure donor cells are injected into damaged
muscle in the hope that they will fuse with the diseased muscle and
create some healthy muscle fibres. Promising results have been obtained
in mouse and dog models with stem cells called ‘mesangioblasts’.
Mesangioblasts are stem cells found in the walls of blood vessels that
under the right conditions can develop into muscle cells. Mesangioblasts
have the ability to travel through the blood stream and make their way
into the muscles. A clinical trial is ongoing in Italy to assess the
safety of transplantation of mesangioblasts (obtained from unaffected
brothers) into DMD patients. The first 6 patients have received
multiple injections of mesangioblasts into an artery. It is
anticipated that the results will be available late 2013.
Challenges with this approach will still
need to be overcome. Transplantation of donor cells will elicit an
immune response (like the transplantation of any tissue into another
person). It may be possible to give drugs that suppress the immune
system. This is standard treatment for individuals receiving an organ
transplant. Unfortunately, chronic treatment with these drugs is not
without side effects. Scientists are also working on ways in which the
patient's own stem cells could be isolated, grown in the lab, the
genetic defect corrected with gene therapy and transplanted back into
It is important to note that there are
currently no licensed stem cell treatments for muscular dystrophy.
There are clinics that offer expensive stem cell treatments but the
safety and benefit has not been tested in clinical trial. This means
the treatment may be ineffective and even dangerous.
Our bodies naturally make a protein similar to dystrophin
called utrophin in small amounts. It is thought that utrophin may be
able to compensate for the lack of dystrophin in boys with DMD.
Research in mice and dogs lacking dystrophin has shown that increasing
the levels of the utrophin protein can prevent muscle damage. Professor
Dame Kay Davies' laboratory at the University of Oxford has been
researching utrophin for more than 20 years. In recent years, in
collaboration with Oxford biotechnology company Summit plc they found a
promising drug - called SMT C1100 - that was able to increase the amount
of utrophin in a mouse model of DMD. SMT C1100 is now in the early
stages of clinical trial – it has been tested in a phase 1 trial in
healthy volunteers and a phase 1b trial started in December 2013 to test
the drug in 12 boys with Duchenne MD. This trial will further test the
safety of the drug and determine the dose to be used in a larger trial
to test if it is effective. More information is available on the Summit plc website
Reducing muscle damage
Various drugs are being investigated for their ability to
treat the symptoms of DMD and slow down disease progression. In DMD the
muscle fibres are continuously damaged when the muscles contract. This
causes inflammation which further damages the muscles leading to
muscle wasting and the accumulation of scar tissue (‘fibrosis’). Drugs
are being researched that could improve the ability of the body to
repair damaged muscle, suppress inflammation and inhibit scar tissue
An example of this approach is a drug
discovered by reseachers in the USA that could replace the
corticosteroid drugs such as prednisolone currently used to treat
Duchenne MD. In studies in mice the drug - called VBP15 - worked better
than prednisolone without the harsh side effects. Clinical trials of
VBP15 are being planned with an expected start date in 2014.
Catena®, (idebenone), an antioxidant, is
in phase 3 clinical trial for Duchenne MD. Another anti-oxidant compound
currently in phase 2/3 clinical trial is Sunphenon
Epigallocatechin-Gallate (EGCg) which is extracted from green tea.