making muscle wasting history

Research Review No. 20

DMD: Past-Present-Future.
A recent review.

Introduction:
In this review of recent publications, I am looking at three interesting papers. The first is a review from Japan by Sugita and Takeda (1), which is especially noteworthy because one of the authors, H. Sugita, was the discoverer of the diagnostic test for Duchenne Muscular Dystrophy (DMD) by showing a correlation of DMD with raised serum levels of creatine phosphokinase (CK) 50 years ago (2). They describe the history of this discovery, which ultimately was based on a suggestion from a colleague. This test is still the basic diagnostic test for DMD.
The second paper to be discussed, deals with the impact of steroids on surgery in patients with DMD (3). Although steroid treatment is known to have complications, it is still the main treatment given to DMD patients.
The final paper (4), which I wish to discuss, deals with structural aspects of the dystrophin molecule, which will have to be taken into consideration when any type of replacement therapy is being considered.

The study and review from Japan:
This is an excellent review of the current situation with regard to DMD research over the last half-century from the discovery of the diagnostic role of CK levels, via the discovery of the dystrophin gene in 1986 to the current studies of attempts to treat DMD and Becker muscular dystrophy (BMD), see Table 1. When these treatments are examined, it is clear that currently the most promising are those involving drugs that provide symptomatic alleviation of the condition but no ‘cure’. However, it is only the exon skipping treatments that are currently considered sufficiently effective in providing possible ‘cures’ for this condition.
The authors thus concentrate in their review on a discussion of exon skipping as a mode of treatment. They give detailed accounts of the chemistries involved in the development of these treatments, stressing the importance of them gaining access to the appropriate cells including the heart cells. The results of studies in mice and dogs are described and it is shown how important these are to gain an understanding of the activities of these drugs. To conclude, I cannot improve on the conclusions reached by these authors and thus quote the last part of their review:
“Because individual DMD patients have different mutations, exon skipping therapy requires a precise evaluation of mutations in the genome and the cDNA, and splicing patterns must be confirmed in each patient’s muscle. In this point, exon skipping is a quite new, personalized therapeutic strategy. As clinicians and researchers involved in the study of muscular dystrophies, one of us for more than 50 years, we are pleased with recent progress in the field and hope that DMD patients benefit from this new therapy in the near future.”

Surgery, Steroids and DMD:
Steroid treatment is still the only general treatment for cases of DMD. In this study from Canada (3), the authors examined the surgical outcomes of boys with DMD. Scoliosis surgery, Achilles tendon lengthening and cataract surgery, were the main surgical treatments examined. It was found that “boys who had received steroid therapy were significantly less likely to undergo spinal surgery, but were subsequently more likely to require cataract surgery”. However, steroid medication did not appear related Achilles tendon lengthening.
The authors conclude that: “The treatment of patients with Duchenne muscular dystrophy with steroids significantly modified their surgical experience.”

The Structure of Dystrophin:
In this Anglo-French study, the authors show that dystrophin interacts with many of the proteins and lipids (fats) in both the membrane as well as the internal structure of the muscle cell. These interactions have shown that there is more to the structure and function of dystrophin than purely to act as a type of scaffolding providing a passive link between the two attachment ends of the molecule. The view had been that it is like a chain linking two points. These studies have shown that dystrophin interacts with a number of other elements of the muscle cell. Although it is not established which under conditions these interactions may occur, the authors consider that further studies are needed to establish the roles of the different parts of the dystrophin molecule. The results of these future studies could affect the outcomes of a number of the treatments currently in progress.


References:

1. Sugita, H. & Takeda, S. (2010) Progress in muscular dystrophy research with special emphasis on gene therapy. Proceedings of the Japan Academy Series B-Physical and Biological Sciences. 86(7):748-756.

2. Ebashi, S., Toyokuma, Y., Momoi, H. and Sugita, H. (1959) High creatine phosphokinase activity of sera of progressive muscular dystrophy. Journal of Biochemistry. 46:103–104.

3. Dooley, J.M., Gordon, K.E. & MacSween, J.M. (2010) Impact of Steroids on Surgical Experiences of Patients With Duchenne Muscular Dystrophy.

4. Le Rumeur, E., Winder, S.J. & Hubert, J.F. (2010) Dystrophin: More than just the sum of its parts. Biochimica et Biophysica Acta-Proteins and Proteomics. 1804(9):1713-1722.




Table 1
Clinical trials for DMD/BMD

Category Interventions Phase
(ClinicalTrials.gov)

Drug Myostatin blocking
MYO-029 Completed; not effective

Read-through
PTC124 Completed; not effective

Gentamicin Completed; not effective

Others
Pentoxifylline Completed; not effective
Idebenone Phase III
Ramipril vs. Carvedilol Phase IV
Coenzyme Q10 and prednisone Phase III
Coenzyme Q10 and lisinopril Phase III
Debio-025 (cyclosporine analogue) Phase IIb

Gene therapy Exon skipping (systemic delivery)
PRO051 (2′-O-MePS AO)(exon 51 skipping)
Phase III

PRO044 (2′-O-MePS AO)(exon 44 skipping) Phase I/II

AVI-4658 (PMO)(exon 51 skipping) Phase IIb

AAV vector Phase I*
rAAV2.5-CMV-Mini-Dystrophin

Cell therapy Satellite cells (myoblasts) Pending
Mesoangioblasts In preparation
Induced pluripotent stem (iPS) cells Experimental


Karl A. Bettelheim
2.9.2010