DMD/BMD - Part 4

Question 1

Is there a cure for DMD?

Answer 1

There is no known cure for DMD at present. However, Patients can be given treatments to improve their quality of life. There are also a number of new treatments for DMD that are currently in development.

Question 2

Why has the development of new treatments for DMD been slow?

Answer 2

Their development has been slow due to the large size of the dystrophin gene and the fact that it is widely expressed in all muscle types and in the central nervous system.

Question 3

What has been set up to help facilitate the development of new treatments for BMD/DMD?

Answer 3

The DMD registry has set up a national database for clinicians, health professionals and researchers to help accelerate the development and delivery of new treatments for DMD and BMD. The project aims to register every person in the UK with DMD or BMD in a secure, legally protected database in order to facilitate a streamlined clinical trial system.

Question 4

Describe the new treatments and developments for DMD/BMD.

Answer 4

1) . Gene Therapy - attempts to insert a functional dystrophin gene into muscle cells. However, this has been hampered by the size of the gene and the vectors that can be used for delivery. There has been some success using smaller versions of dystrophin called micro-dystrophin in mice and more recently in dogs.
2) . Upregulation of dystrophin homologue, utrophin - it has not been possible to upregulate the expression to therapeutic levels.
3) . Chimeric oligonucleotides - have also been investigated. Are used to repair genes in situ through cellular DNA repair activity.
4) . Antisense oligonucleotides
5) . Read-through drugs e.g. aminoglycosides

The most promising treatments have been through the use of antisense oligonucleotides and read-through drugs.

Question 5

Describe the use of antisense oligonucleotides in the treatment of DMD.

Answer 5

• Antisense oligonucleotides aim to alter the splicing of the DMD precursor mRNA by targeting exons affected by the deletion/mutation.
• They cause skipping of the targeted exon from the mature mRNA and stop the mutation causing a frameshift. This results in the conversion of the DMD phenotype to a BMD phenotype.
• The antisense RNA molecules block motifs involved in normal splicing.
• Each deletion requires different antisense oligonucleotides which as been thought to be a limiting factor in tis therapy. However, there are hotspots so the skipping of a small number of exons can be applicable to a relatively large number of patients.
• Exon 51 skipping has been tested in clinical trials. It is applicable to the largest group of DMD patients (13%).
• A problem with antisense oligonucleotides is that they only have a transient effect and have to be repeatedly administered.
• Highly variable degree of restoration within and between muscles. Low efficiency for heart muscle.
• The success of this treatment depends on muscle tissue still being present, as it would not be expected to be able to reverse the loss of muscle.

Question 6

Describe the use of read-through drugs in the treatment of DMD.

Answer 6

• Read-through drugs induce the protein making machinery to “read-through” premature stop codons, allowing the full length protein to be made.
• This approach is only appropriate for patients with a point mutation that leads to a premature stop codon.
• Aminoglycoside antibiotics e.g. gentamicin can read through premature termination codons resulting in full length protein. These have been trialled, but they have bad side effects and they cannot be administered orally.
• Ataluren (formely PTC124) is a non-aminoglycoside specifically designed to read through premature stop codons. It is orally bioavailable and is considerably less toxic than gentamicin. In phase II trials for DMD results have suggested that it slows the loss of walking ability. However, other analyses of the data suggests that it doesn’t. This is a promising treatment for a relatively small percentage of DMD patients.

Question 7

Describe DMD newborn screening.

Answer 7

• DMD newborn screening commenced in Wales in 1990. For this testing parents had to explicitly consent. CK levels were tested on the routine newborn screening blood spot.
• Samples showing a bloodspot CK value of 200U/L or above are re-assayed again in duplicate, and those with an average value of 250U/L or greater across the 3 samples recieve a follow up serum CK test at 6-8 weeks. If serum CK levels are normal, DMD is not suspected. If serum CK is raised, DMD is suspected, and the child goes on to have mutational analysis.
• The Welsh screening system identified around four boys with DMD each year.
• Sensitivity was about 83% meaning around 17% of DMD cases were missed.
• Specificity was high at around 99.98%.
• The problem with the test was the low positive predictive value of around 41%. This meant that for every true positive there was roughly one false positive.
• The test picked up mainly newborns with DMD, but also a smaller number or newborns with BMD or other dystrophinopathies.
• Wales screening ceased in 2011. This was due to the quality reassurance scheme no longer being available and to problems with obtaining commercial reagents.
• The 2011 review by the UK National Screening Committee did not recommend introducing the newborn screening UK wide.