Portrait of Duchenne – Ataluren a promising treatment for DMD

Ellen Welch, PhD

Group leader biology at PTC Therapeutics, South Plainfield, New Jersey, USA


In this fourth interview of our series “Portrait of Duchenne”, La Force DMD talks with Ellen Welch, Ph.D., Group leader biology at PTC Therapeutics. She has been working on a treatment for DMD called ataluren (Translarna™). She earned her Ph.D. at the University of Massachusetts Medical School, where she worked on nonsense mutations and how they affect gene expression. 


Already approved and reimbursed in Europe

Ataluren is a treatment for Duchenne muscular dystrophy (DMD) that has been approved for use in Europe and even reimbursed in the UK. It is currently under the FDA review for marketing approval in the USA. Unfortunately, PTC Therapeutics has not filed an application to market ataluren in Canada. We met the PTC Therapeutics team to gather information to understand how exactly this treatment works. New clinical trials are opening for children with DMD. We hope this treatment will be available soon for the Canadian DMD community.


A treatment for nonsense mutation

Ataluren is the first treatment to address an underlying cause of DMD: a nonsense mutation. The nonsense mutation occurs about 13% of the DMD population. As you probably know, DMD is a rare, progressive genetic disorder. Children born with DMD do not produce enough dystrophin, an important structural component of muscle, causing muscle cells to break down and die. Some cases of DMD are caused by nonsense mutations, which are errors in the genetic code that prematurely stop the production of dystrophin.

Our goal, with this interview, is to help you understand key information about the nonsense mutation and how the treatment works.


In the video, Dr. Ellen Welch answers our questions about nonsense mutation and ataluren


What is a nonsense mutation?

So I think what you first have to understand is that all the genetic information in the cells is encoded in DNA. You make a copy of DNA into RNA (ribonucleic acid) and then RNA is the template that the cell uses in order to make a protein. So when you have a nonsense mutation in a gene – so if you took the DMD gene, for instance, and you get a point mutation in DMD – when that DNA is copied into RNA, that point mutation can now be part of the RNA that becomes what’s called a premature stop codon. So this is what Anakin has: he has a premature stop. So what does that mean? It means when the cell uses this piece of RNA to make a protein, that it cannot make a full-length protein because it has this premature stop signal. It’s got a signal in the cell that says stop making the protein. And that signal is in the wrong place.


How does ataluren help the production of dystrophin?

And what dystrophin does is it links the membrane of the muscle to the inside of the cell – acts as like a shock absorber – so when you walk, your muscle cells don’t break open. So when you only have one part of dystrophin, it can’t make that link. So if you can read through the premature stop, now you can trick, what ataluren does, it tricks the cell and says don’t stop there, keep going. And then you can make the full-length protein, so now you can link the inside and the outside of the cell together, and that helps to stabilize the muscle. So what we know from what ataluren does is, when you translate – encounter the premature stop codon – the cell machinery is able to insert another amino acid, one of the building blocks for a protein, there. So when it inserts that building block, then it can go on and make the rest of the protein normally. You just have to get through that one hurdle, but that hurdle is a component of the cellular machinery that’s very highly regulated. Because it’s important for the cell, when it really comes to the normal stop signal, to stop. Otherwise, you’ll make these weird proteins and the cell could be very toxic. So, you have to overcome this sort of desire of the cell to stop there. So, ataluren does overcome that. It doesn’t restore it to a wild-type level, but we think it restores it enough to stabilize the disease, and that’s what we’ve shown in our clinical trials to date. So, it just tricks the cell a little bit to make a full-length protein.


How do you envision the future for people with DMD?

I think it’s very optimistic. I think that there are a lot of companies who are making drugs for DMD now. I think there’s ataluren for the read-through population. I think there’s exon skipping that’s coming. Other people are working on things that, other proteins that you can up-regulate to replace dystrophin like utrophin. They’re doing that. So, I think there’s a lot of, there’s a nucleus of people that are basically working from many different directions to identify treatments for DMD. So, I think it’s pretty optimistic, even for kids now. I think it will just get better. But I think I’m fairly optimistic.


Actions to help access to ataluren in Canada

There are a couple of things that you can do right now to help us promote access to ataluren in Canada. Here are three actions that you take right now that will help the DMD community:

1- Be aware of your genetic profile. If you don’t have it, ask your doctor.

2- Get in touch with us. E-mail us, follow-us. We’ll be documenting government approval processes

3- Spread the word. Share our content, share pertinent information, and tell your stories.


Up next:

Our next portrait: Joanne Donovan, Chief Medical Officer and Senior Vice President, Clinical Development, Catabasis Pharmaceuticals

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We thank the PTC Therapeutics team, who received us with open arms to conduct a series of interviews.

We thank Allain Lagadic and Daniel Cooper


PTC Therapeutics

Ataluren (Translarna™)

ACT DMD Clinical Trial of Translarna™ (ataluren)