Prosensa publishes encouraging Duchenne exon skipping trial

Hi Emma,

I’m going to need to “phone a friend” on this one. I’ll ask one of the clinicians involved in the exon skipping trials. It is very complicated and I’d hate to give you the wrong information.

I’ll get back to you as soon as I hear.

Best wishes,
Kristina.

The number of boys affected by a mutation plays a role in the decision which molecular patch to develop next. But also it may be that certain exons (sections of the gene) are easier to skip than others, or there may be other safety related factors involved. For example the molecular patch for an exon might be toxic and cause serious side effects. These factors are not known until they do the preclinical tests in the laboratory.

Below is part of a table I have copied from a paper on the applicability of skipping certain exons. The prevalence is the percentage of boys with Duchenne that could be treated by skipping that exon. The list goes on and on to ranking 120 (0.02% of boys) but I have just pasted the first 21 here. As you can see the molecular patches that are currently being developed – skipping exons 51, 50, 44, 45, 52, 53 and 55 – are in the top 11, each being able to treat more than 2%.

Rank Exon Prevalence
1 51 13.0%
2 45 8.1%
3 53 7.7%
4 44 6.2%
5 46 4.3%
6 52 4.1%
7 50 4.0%
8 43 3.8%
9 6 and 7 3.0%
10 8 2.3%
11 55 2.0%
12 2 1.9%
13 69 and 70 1.4%
14 19 and 20 1.1%
15 45 and 51 1.1%
16 58 and 59 1.1%
17 17 1.0%
18 7 1.0%
19 65 and 66 1.0%
20 43 and 44 0.9%
21 12 0.8%

This list also includes skipping multiple exons at once – we don’t know how effective this will be and if this will be more complicated. It is impossible to predict when they might get to developing molecular patches for other exons as it depends on how the current clinical trials go.

It is hoped that once exon skipping for one exon is proven to be effective, it will be relatively quick to develop molecular patches for the other exons. The researchers are working with the regulatory authorities to get a modified approval process in place. It just won’t be possible to conduct large clinical trials for all of the patches, it will be too expensive and there won’t be enough patients to go through the usual, extensive clinical trial process.

Another factor for the success of exon skipping is whether the resulting dystrophin protein will be able to work well enough to improve muscle strength. Exon skipping works because dystrophin is such a large gene (79 exons) and many of the exons in the middle are the same piece of code repeated over and over – exons 8 to 61. So if you’re missing some of those repetitive exons it doesn’t matter so much and the gene can still work relatively ok with symptoms similar to Becker muscular dystrophy. A man with Becker muscular dystrophy was known to be missing almost half of the exons in the middle of the dystrophin gene and was still able to walk into his 60s. However, some parts of the gene, especially at the ends are known to be crucial. For example they interact with other proteins in the muscle. So if the exons before number 8 and after 61 are disrupted then exon skipping is unlikely to be successful. Other approaches such as gene therapy using a virus or utrophin upregulation are more promising therapies in these cases.

Kristina.