Research Review No. 93.
A further study full of hope.
The Studies:
The authors of the first study to be discussed (1) from U.S.A. investigated
the use of adeno-associated virus (AAV) to deliver DNA carrying information, that
can treat all muscles of the patients with Duchenne muscular dystrophy (DMD).
Such delivery has been successfully carried out over a decade ago in dystrophic
mice, however difficulties in larger mammals ‘has been challenging’. In this study
the authors used micro-dystrophin (μDys) in AAV to treat three juvenile about
two-month old dogs with DMD. The doses of 1.92–6.24 × 1014 viral genome
particles/kg were given intravenously under transient or sustained immune
suppression. The DMD dogs tolerated the injection well and their growth was not
altered. Both haematology and blood biochemistry were unremarkable and no
adverse effects were noted. The paper is well illustrated with both photographs
and tables demonstrating that: ‘Widespread muscle transduction was seen in
skeletal muscle, the diaphragm and heart for at least 4 months (the end of the
study).’ In their summary they state that: ‘systemic AAV gene transfer is safe and
efficient in young adult dystrophic large mammals.’ They consider that: ‘this may
translate to bodywide gene therapy in paediatric patients in the future’.
Another approach to the treatment of DMD is presented in the second
paper to be discussed in this review (2). The authors, who are from a number of
countries and all experts in the field of DMD therapy, discuss in this study the
role of antisense oligonucleotides (AONs), which show so much promise in their
ability to ‘correct’ genetic diseases through exon-skipping. They draw attention to
the fact that currently there are clinical trials in progress explicitly examining
these treatments for DMD. They note that at present one of disadvantages of
these processes is the poor uptake by the tissues of the AONs.
In this study they present a new type of AON made with tricyclo-DNA
(tcDNA). This had been shown to display ‘unique pharmacological properties and
unprecedented uptake by many tissues after systemic administration’. They were
able to demonstrate this in the mouse-model of DMD. They note that currently
the naked AONs fail to enter the heart or cross the blood-brain barrier, However,
these studies have found that ‘systemic delivery of tcDNA-AONs promotes a high
degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a
lesser extent, the brain’. Both physiological improvement of cardio-respiratory
functions as well as a correction of behavioural features in DMD model mice
were noted.
In conclusion, they consider that these tcDNA-AONs provide a chemistry
that is ‘particularly attractive as a potential future therapy for patients with DMD
and other neuromuscular disorders’.
References:
1)
Yue, Y., Pan, X., Hakim, C.H., Kodippili, K., Zhang, K., Shin, J.-H., Yang,
H.T., McDonald, T. & Dongsheng Duan, D. (2015) Safe and bodywide muscle
transduction in young adult Duchenne muscular dystrophy dogs with adenoassociated virus . Human Molecular Genetics. HMG Advance Access published
August 18, 2015.
2)
Goyenvalle, A., Griffith, G., Babbs, A., El Andaloussi, S., Ezzat, K., Avril,
A., Dugovic, B., Chaussenot, R., Ferry, A., Voit, T., Amthor, H., Bühr, C.,
Schürch, S., Wood, M.J.A., Kay E Davies, K.E., Vaillend, C., Leumann, C. &
Garcia, L. (2015) Functional correction in mouse models of muscular dystrophy
using exon-skipping tricyclo-DNA oligomers. Nature Medicine. (Advance Access
Publication Date: 11 August 2015).
Note:
You may have noticed that these two studies have been released prior to full
publication and I would like to thank the authors for making these important
studies available to me.
Karl A. Bettelheim
6.9.2015