Download DMD Reviews 107 - Action Duchenne

Research Review No. 107.
Treatments for Duchenne Muscular Dystrophy (DMD) galore, Part 1.
The Studies:
A recent study from U.S.A. (1) designed “to assess safety and efficacy of
deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular
dystrophy (DMD)” found that “after 12 weeks of treatment, PRED and both doses
of DFZ improved muscle strength compared with placebo. Deflazacort was
associated with less weight gain than PRED.” This well-thought through study
should be very useful when decisions on ways of treating DMD are made.
While studies, like the one above are essential prior to deciding on their
use to treat patients, appropriate animal studies have to be considered, which
mimic as far as possible the human situation. The six-minute walk test (6MWT)
has been used in patients with DMD for a number of years. A recent study from
U.S.A developed this for cross-bred golden retrievers (2), carrying a mutation in
their dystrophin gene (GRMD). This thorough study’s “results correlated with
other functional outcome parameters for all dogs, but not GRMD alone.” They
caution that “while these data generally support use of the 6MWT as a biomarker
for preclinical GRMD treatment trials, limitations relate to its failure to correlate
with other tests for GRMD dogs alone and apparent lack of sensitivity to detect
smaller levels of efficacy.” Further studies “such as these, should further clarify
the 6MWT’s value as an outcome parameter in GRMD.”
Animal studies are essential for the development of treatments such as
DMD and the authors of the next study to be discussed, also from U.S.A. (3)
used a mutant zebrafish (sapje), “Sapje zebrafish lack the protein dystrophin and
are the smallest vertebrate model of Duchenne muscular dystrophy (DMD).”
Their recently published studies show that “the severe contractile deficits of sapje
larvae represent novel physiological endpoints for therapeutic drug screening”.
In a short discussion Cy A. Stein, a member of the Editorial Board of the
scientific journal ‘Molecular Therapy’, comments on the problems both social and
economic when faced with a potential drug to treat DMD. The drug Eteplirsen
now renamed Exondys 51, targets “the splice-donor region of exon 51, induces
skipping of exon 51. This yields an in-frame, truncated, yet partially functional
dystrophin protein, similar to what is found in Becker muscular dystrophy, a much
less severe form of the disease.” The problem of making the drug available by
the FDA (Food and Drug Administration) is highlighted by him thus: “Janet
Woodcock, Director of the FDA’s Drug Division, overruled her own scientists, and
Robert Califf, the FDA commissioner, agreed with her. Eteplirsen, now renamed
Exondys 51, was approved, to the delight of many and the fury of some.” They
lamented the FDA’s decision as “this isn’t even science.” Due to the complexity
of the discussion Stein concludes thus: ”We should know if Exondys 51 will
produce in about the year 2020. My believe is that it ultimately will.”
The very recent emergence of the technique of gene editing being applied
to DMD research is being reviewed in the study from Canada (5). They consider
that “these studies represent proof of principle that CRISPR/Cas9 technology can
be used to correct the DMD gene and to restore the expression of an internally
truncated Dys protein”, although caution is advised. They do claim that:”
CRISPR/Cas9 technology may lead to the development of a permanent
treatment for DMD”. They do stress that: “Future experiments developing
CRISPR/Cas9 therapy for DMD will have to be done in an adequate mouse
model such as the hDMD/mdx mouse, containing in the mdx background the
human DMD gene with deletion of one or several exons as observed in DMD
patients.”
It is indeed heartening to see so much research seeking the best for
people with DMD being carried out. It is the hope of all of us that meaningful
results and treatments will emerge soon.
References:
1.
Griggs, R.C., Miller, J.P., Greenberg, C.R., Fehlings, D.L., Pestronk, A.,
Mendell, J.R., Moxley, R.T., King, W., Kissel, J.T., Cwik, V., Vanasse, M.,
Florence, J.M., Pandya, S., Dubow, J.S. & Meyer, J.M. (2016) Efficacy and
safety of deflazacort vs prednisone and placebo for Duchenne muscular
dystrophy. Neurology. 87(20):2123-2131.
2.
Acosta, A.R., Van Wie, E., Stoughton, W.B., Bettis, A.K., Barnett, H.H.,
LaBrie, N.R., Balog-Alvarez, C.J., Nghiem, P.P., Cummings, K.J. & Kornegay,
J.N. (2016) Use of the six-minute walk test to characterize golden retriever
muscular dystrophy. Neuromuscular Disorders. 26(12):865-872.
3.
Widrick, J.J., Alexander, M.S., Sanchez, B., Gibbs, D.E., Kawahara, G. &
Beggs, A.H. (2016) Muscle dysfunction in a zebrafish model of Duchenne
muscular dystrophy. Physiological Genomics. 48(11):850-860.
4.
Stein, C.A. (2016) Eteplirsen Approved for Duchenne Muscular Dystrophy:
The FDA Faces a Difficult Choice. Molecular Therapy. 24(11):1884-1885.
5.
Tremblay, J.P., Lyombe-Engembe, J.P., Duchene, B. & Ouellet, D.L.
(2016) Gene Editing for Duchenne Muscular Dystrophy Using the CRISPR/Cas9
Technology: The Importance of Fine-tuning the Approach. Molecular Therapy.
24(11):1888-1889.
Karl A. Bettelheim
16.3.2017