Research Review No. 86.
Recent exciting new Developments.
A general oveview.
Introduction:
There have been so many new developments over the last few months,
that I have been overwhelmed, so I have decided to try a new format. To give the
full reference and a one to two sentence comment. Thus reading the authors’ title
and my comment based on their conclusions will give you the flavour of the
study.
The Studies:
1.
Landfeldt, E., Lindgren, P., Bell, C.F., Schmitt, C. Guglieri, M., Straub, V.,
Lochmüller, H. & Bushby, K. (2014) The burden of Duchenne muscular
dystrophy: An international, cross-sectional study. Neurology. 83(6):529-536.
Comment:
This is a unique study of the substantial economic cost to the community. They
estimated that the mean annual household burden of DMD was between $58,440
and $71,900.
2.
Davidson, ZE., Ryan, M.M., Kornberg, A.J., Sinclair, K., Cairns, A.,
Walker, K.Z. & Truby, H. (2014) Observations of body mass index in Duchenne
muscular dystrophy: a longitudinal study. European Journal of Clinical Nutrition.
68(8):892-897.
Comment:
This study examined the effect of steroid treatment on the body mass index
(BMI) on boys with DMD. They noticed a decline in BMI in these boys with
decreasing age.
3.
Buckland, K.F. & Gaspar, H.B. (2014) Gene and cell therapy for children New medicines, new challenges? Advanced Drug Delivery Reviews, 73:162-169.
Comment:
They note the advances, which are being made in the treatment of genetic
disorders, and mention the exon-skipping advances in progress at present.
4.
Waugh, T.A., Horstick, E., Hur, J., Jackson, S.W., Davidson, A.E., Li, X. &
Dowling, J.J. (2014) Fluoxetine prevents dystrophic changes in a zebrafish model
of Duchenne muscular dystrophy. Human Molecular Genetics. 23(17):46514662.
Comment:
They screened a number of potential drugs on the Zebrafish model DMD, which
they describe as: ‘as a powerful model for drug discovery
5.
Disterer, P., Kryczka, A., Liu, Y., Badi, Y.E., Wong, J.J., Owen, J.S. &
Khoo, B. (2014) Development of therapeutic splice-switching oligonucleotides.
Human Gene Therapy. 25(7):587-598.
Comment:
The authors note that up to 50% of human genetic diseases are due to mutations
that affect splicing. Therefore use of synthetic splice-switching oligonucleotides to
target nuclear pre-mRNA molecules to change exon splicing and generate an
alternative protein isoform might be a potential new approach to treat DMD.
5.
Yokota, T., Takeda, S., Lu, Q.-L., Partridge, T.A., Nakamura, A., &
Hoffman, E.P. (2014) A Renaissance for Antisense Oligonucleotide Drugs in
Neurology, Exon Skipping Breaks New Ground. Archives in Neurology. 66(1):3238.
Comment:
These authors note that with long-standing barriers to the use of Exon Skipping
Breaks drugs being successfully circumvented, attention should now turn
towards the up-scaling of production, long-term toxicity studies, and the
challenges to traditional drug regulatory attitudes presented by these tightly
targeted sequence-specific drugs.
6.
Landfeldt, E., Lindgren, P., Bell, C.F., Schmitt, C. Guglieri, M., Straub, V.,
Lochmüller, H. & Bushby, K. (2014) The burden of Duchenne muscular
dystrophy: An international, cross-sectional study. Neurology. 83(6):529-536.
Comment:
The economic burden of DMD was assessed in this study, using data from cases
from U.K., U.S.A., Germany and Italy. They estimated the mean annual out-ofpocket payments at between $3,490 and $14,390, and these variations were
primarily driven by differences in the degree of cost-sharing in the national health
care systems, but also the type and intensity of health care received.
7.
Buckland, K.F. & Gaspar, H.B. (2014) Gene and cell therapy for children New medicines, new challenges? Advanced Drug Delivery Reviews, 73:162-169.
Comment:
In this review, the range of possible gene and cell therapy applications is
considered by these authors to be expanding at an extremely rapid rate. They
claim that advanced therapy medicinal products (ATMPs) are currently the
hottest topic in novel medicines, particularly for inherited diseases. Paediatric
patients are expected to gain enormously from these novel therapies. It now
seems plausible to develop a gene or cell therapy for a vast number of inherited
diseases, and there are a wide variety of potential gene and cell therapies in
various stages of development. They refer to reviews specifically dealing with
DMD, such as one by Benedetti’s review of last year.
(S. Benedetti, H. Hoshiya, F.S. Tedesco, Repair or replace? Exploiting novel
gene and cell therapy strategies for muscular dystrophies, FEBS J. 280 (2013)
4263-80.)
8.
Arpan, I., Willcocks, R.J., Forbes, S.C., Finkel, R.S., Lott, D.J., Rooney,
W.D., Triplett, W.T., Senesac, C.R., Daniels, M.J., Byrne, B.J., Finanger, E.L.,
Russman, B.S., Wang, D.-J., Tennekoon, G.I., Walter, G.A., Sweeney, H.L. &
Vandenborne, K. (2014) Examination of effects of corticosteroids on skeletal
muscles of boys with DMD using MRI and MRS. Neurology. 83(11):974-980.
Comment:
Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy
(MRS) are valuable non-invasive methods of measuring biological parameters. In
this study, these techniques were examined for their ability to detect the
therapeutic effects of corticosteroids in reducing inflammatory processes in
skeletal muscles of boys with DMD and their studies confirmed the suitability of
these techniques for such determinations.
9.
Doorenweerd, N., Straathof, C.S., Dumas, E.M., Spitali, P., Ginjaar, I.B.,
Wokke, B.H., Schrans, D.G., van den Bergen, J.C., van Zwet, E.W., Webb, A.,
van Buchem, M.A., Verschuuren, J.J., Hendriksen, J.G., Niks, E.H. & Kan, H.E.
(2014) Reduced cerebral gray matter and altered white matter in boys with
Duchenne muscular dystrophy. Annals of Neurology. 76(3):403-411.
Comment:
They used quantitative magnetic resonance imaging (MRI) to study brain
microstructure in DMD cases. They found that these individuals had smaller total
brain volume, smaller gray matter volume, lower white matter fractional
anisotropy, and higher white matter mean and radial diffusivity than healthy
controls. They also note that DMD patients also performed worse on
neuropsychological examination. The role of Dystrophin isoforms in brain
physiology is also discussed.
10a. Voit, T., Topaloglu, H., Straub, V., Muntoni, F., Deconinck, N , Campion,
G., De Kimpe, S.J., Eagle, M., Guglieri, M., Hood, S., Liefaard, L., Lourbakos, A.,
Morgan, A., Nakielny, J., Quarcoo, N., Ricotti, V., Rolfe, K., Servais, L., Wardell,
C., Wilson, R., Wright, P. & Kraus, J.E. (2014) Safety and efficacy of drisapersen
for the treatment of Duchenne muscular dystrophy (DEMAND II): an exploratory,
randomised, placebo-controlled phase 2 study. The Lancet. Neurology.
13(10):987-996.
10b. Hoffman, E. (2014) A rebirth for drisapersen in Duchenne muscular
dystrophy? The Lancet. Neurology. 13(10):963-965.
Comment:
The in 10a describe a clinical trial with the exon-skipping drug drisapersen, while
10b is a comment on the 10a study. Drisapersen (GSK2402968; PRO051) is a
2ʹ-O-methylphosphorothioate (2OMePS) RNA oligonucleotide targeting exon 51.
The studies found that continuous drisapersen resulted in some benefit in six
minute walk test (6MWD) compared to the placebo at week 25. The safety
findings were similar to those from previous studies. The authors consider that
the ambulation improvements in this young population with early-stage DMD are
encouraging but need to be confirmed in larger studies.
In the comment (10b) it is noted that there was no improvement observed in the
other motility rests, but the results are nevertheless considered encouraging.
Karl A. Bettelheim
8.12.2014
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