Research Review No. 87.
More Recent exciting new Developments.
A general oveview.
Introduction:
There have been more papers published recently so I felt that it would be
appropriate to draw the Duchenne communitiy’s attention to them.
The Studies:
1.
Manning, J., Kulbida, R., Rai, P., Jensen, L., Bouma, J., Singh, S.P.,
O'Malley, D. & Yilmazer-Hanke, D. (2014) Amitriptyline is efficacious in
ameliorating muscle inflammation and depressive symptoms in the mdx mouse
model of Duchenne Muscular Dystrophy. Experimental physiology. 99(10):13701386.
Comment:
The authors note that there is no doubt about the antidepressant action
amitriptyline and that it comes with many side-effects. Therefore they advise
caution in its use in patients with DMD. Nevertheless, their studies indicate that
amitriptyline may have positive effects on mood in mdx mice, which they link with
changes in brain physiology. Additionally, they found that, amitriptyline reduced
muscle inflammation, which may not only contribute to improvements in skeletal
muscle function but also reduce emotional disturbances related to inflammation.
2.
Aartsma-Rus, A., Ferlini, A., Goemans, N., Pasmooij, A.M. G., Wells, D.J.,
Bushby, K., Vroom, E. & Balabanov, P. (2014) Translational and Regulatory
Challenges for Exon Skipping Therapies. Human Gene Therapy. 25(10):885-892.
Comment:
This study discusses the challenges of which ‘are currently impeding the
therapeutic development of antisense-mediated exon skipping approaches for
rare diseases’. The comparatively low numbers of patients and the poor
knowledge of the natural history of DMD. Also the fact that the antisense
oligonucleotide (AON)-mediated exon skipping approach generally requires the
AONs to act in a mutation specific manner, indicates that these AONs have to be
designed for each specific condition. In this paper they summarize the report
from a workshop entitled ‘‘Networking towards clinical application of antisensemediated exon skipping for rare diseases.”
3.
Bushby, K., Finkel, R., Wong, B., Barohn, R., Campbell, C., Comi, G.P.,
Connolly, A.M., Day, J.W., Flanigan, K.M., Goemans, N., Jones, K.J., Mercuri,
E., Quinlivan, R., Renfroe, J.B., Russman, B., Ryan, M.M., Tulinius, M., Voit, T.,
Moore, S.A., Lee S.H., Abresch, R.T., Coleman, K.L., Eagle, M., Florence, J.,
Gappmaier, E., Glanzman, A.M., Henricson, E., Barth, J., Elfring, G.L., Reha, A.,
Spiegel, R.J., O'donnell, M.W., Peltz, S.W. & Mcdonald, C.M. for the PTC124GD-007-DMD Study Group. (2014) Ataluren treatment of patients with nonsense
mutation dystrophinopathy. Muscle & Nerve. 50(4):477-487.
Comment:
The authors comment that only about 13% of DMD paptients have their
condition due to so-called ‘Nonsense Mutations’. In these mutations, a codon for
a specific amino acid is replaced by a ‘Stop Codon’, which causes the production
of dystrophin to stop at this point. The drug Ataluren was designed to override
these nonsense mutations and in this paper the authors report on a clinical trial
on the use of Ataluren. In this first such investigation the authors note that
‘ataluren offers promise as a treatment for this orphan genetic disorder with high
unmet medical need.
4.
Vianello, S., Bouyon, S., Benoit, E., Sebrié, C., Boerio, D., Herbin, M.,
Roulot, M., Fromes, Y. & de la Porte, S. (2014) Arginine butyrate per os protects
mdx mice against cardiomyopathy, kyphosis and changes in axonal excitability.
Neurobiology of Disease. 71:325-333.
Comment:
Arginine butyrate (AB) is a drug, which is currently used for the treatment
of sickle cell anemia in children. The authors studied in mdx mice, the effects of
the oral administration of AB on cardiomyopathy, vertebral column deformation
and electromyographic abnormalities. The results of their studies “suggest that
AB could be a potential treatment for DMD patients.”
5.
Feder, D., Rugollini, M., Santomauro, A.Jr., Oliveira, L.P., Lioi, V.P., Dos
Santos, R., Ferreira, L.G., Nunes, M.T., Carvalho, M H., Delgado, P.O.,
Carvalho, A.A.S. & Fonseca, F.L.A. (2014) Erythropoietin reduces the expression
of myostatin in mdx dystrophic mice. Brazilian Journal of Medical and Biological
Research = Revista Brasileira De Pesquisas Medicas E Biologicas/Sociedade
Brasileira de Biofisica. 47(11):966-971.
Comment:
Erythropoietin (EPO) is a hormone, regulates red blood cell production by
inhibiting the programmed cell death (apoptosis) of the red blood cells. EPO also
exerts regulatory effects in cardiac and skeletal muscles. They tested the
possible therapeutic beneficial effect of recombinant EPO (rhEPO) in mdx mice.
The gene expression for myostatin, transforming growth factor-1, and tumor
necrosis factor- was determined. They observed no increase in muscle
strength, but they did find a significant reduction in myostatin, which inhibits
muscle differentiation and growth in the process known as myogenesis.
6.
Larcher, T., Lafoux, A., Tesson, L., Remy, S., Thepenier, V., Francois, V.,
Le Guiner, C., Goubin, H., Dutilleul, M., Guigand, L., Toumaniantz, G., De Cian,
A., Boix, C., Renaud, J.-B., Cherel, Y., Giovannangeli, C., Concordet, J.-P.,
Anegon, I. & Huchet, C. (2014) Characterization of Dystrophin Deficient Rats: A
New Model for Duchenne Muscular Dystrophy. PLOS ONE. 9(10):e110371.
Comment:
There are few animal models of DMD, which are mainly pigs and dogs,
which are very expensive and mice, though cheep but which only partially mimic
the human condition. This study developed mutations in rats targeting exon 23.
In all aspects these rats demonstrated similar effects as in the human condition
and the authors claim that these “rats represent a new faithful small animal
model of DMD”.
7.
Leung, D.G., Herzka, D.A., Thompson, W.R., He, B., Bibat, G.,
Tennekoon, G., Russell, S.D., Schuleri, K.H., Lardo, A.C., Kass, D.A.,
Thompson, R.E., Judge, D.P. & Wagner, K.R. (2014) Sildenafil Does Not
Improve Cardiomyopathy in Duchenne/Becker Muscular Dystrophy. Annals of
Neurology. 76(4):541-549.
8.
Witting, N., Kruuse, C., Nyhuus, B., Prahm, K.P., Citirak, G., Lundgaard,
S.J., von Huth, S., Vejlstrup, N., Lindberg, U., Krag, T.O. & Vissing, J. (2014)
Effect of Sildenafil on Skeletal and Cardiac Muscle in Becker Muscular
Dystrophy. Annals of Neurology. 76(4):550-557.
Comment:
These two studies, which followed each other both deal with the use of
Sildenofil as a possible therapeutic drug for DMD or BMD. sildenofil is also sold
as Viagra. It had been found previously that sildenofil’s inhibition of
phosphodiesterase 5 (PDE5) improves cardiac function in mouse models of
Duchenne and Becker muscular dystrophies (DBMD). In order to determine,
whether this also applies to humans, the authors of paper 7, conducted a fully
randomized, double-blind, placebo-controlled trial. The results showed no
statistically significant differences between the different groups. They note with
caution that “this trial suggests that sildenafil is unlikely to improve cardiac
function in adults with DBMD.”
Similarly in paper 8, the authors, who conducted a similar trial on BMD
patients found that such treatment “showed no effect of sildenafil on blood flow,
maximal work capacity, and heart function in adults with BMD.”
9.
Fairclough, R.J., Guiraud, S., Squire, S.E., Babbs, A., Edward, B., Shah,
N., Bracchi, A., Wilson, F.X., Horne, G., Robinson, N., Araujo, N., Hewings, D.S.,
Vuorinen, A., Davies, S.G., Wynne, G.M., Russell, A.J., Tinsley, J. & Davies, K.E.
(2014) New orally available compounds which modulate utrophin expression for
the therapy of Duchenne muscular dystrophy (DMD). Neuromuscular Disorders.
24(9-10):821-821.
Comment:
This is not a full paper, just an abstract from a conference, but I thought
the conclusions might be useful for the DMD community.
They report that by pharmacologically modulating the dystrophin-related
protein utrophin, they might develop a therapy applicable to all DMD patients. In
partnership with Summit plc they had previously developed the drug SMT C1100;
which is a small molecule acting as a utrophin modulator, that reduced dystrophic
symptoms in the mdx mouse and it has ‘successfully completed a Phase 1a trial’.
Currently humans with DMD are participating in a phase 1b trial.
They have significantly improved their screening technique and are now
investigating a second generation of molecules and very promising results with
new molecules are being obtained.
10. Mendell, J.R., Lowes, L.P., Alfano, L., Saoud, J., Duda, P. & Kaye, E. (2014)
Pulmonary function is stable through week 120 in patients with Duchenne
muscular dystrophy (DMD) treated with exon-skipping drug eteplirsen in phase
2b study). Neuromuscular Disorders. 24(9-10):828-829.
Comment:
This is another conference paper in which the authors report on the
pulmonary (lung) function of patients with DMD, who had been treated with the
exon-skipping drug, eteplirsen, for 120 weeks as part of the phase 2b clinical
trial. The 12 boys under treatment were randomised as required for such a trial.
The authors report that the results of the study showed that “Those who were
eteplirsen dosed for up to 120 weeks demonstrated stability on PFT [pulmonary
function tests] measure contrary to a steady decline expected in DMD patients of
this age”.
Karl A. Bettelheim
15.12.2014
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