17th April 2019

You may remember that in 2017, Duchenne UK and Joining Jack teamed up with Charley’s Fund to fund research into the potential of neutrophil elastase inhibitors (NEIs) as a treatment for Duchenne Muscular Dystrophy (DMD). The joint grant was for £71,700.

Dr. Dada Pisconti, currently of Stony Brook University, and her team of scientists had a hypothesis that this type of therapy – already in clinical trials for other diseases including cystic fibrosis and COPD (conditions that cause breathing difficulties) – might also help boys with Duchenne. 

Our grant helped cover several early but critical steps that need to happen to evaluate whether this approach can help slow Duchenne’s progression. The work we funded — which was also supplemented by funding from the Medical Research Council — had two key phases: (1) evaluate which of 3 different NEIs has the most potential and (2) investigate the efficacy of this specific NEI in a mouse model of Duchenne.

Results from the study are beginning to come in, and on Tuesday 16th April Dr. Pisconti presented preliminary data analyses at the 2019 MDA Scientific Conference in Orlando, Florida. It’s important to note that data analysis is not completely finalised yet, and the results still need to go through a peer review process in which external parties help evaluate the findings. At this early stage, the bottom line is that the results so far look promising. Mice treated with a combination of NEI and standard-of-care steroid prednisolone performed better on certain functional tests than with prednisolone alone.

Also, certain biological markers indicate that adding an NEI treatment to a steroid regimen may increase steroids’ efficacy while also decreasing their toxicity. This is encouraging because chronic steroid use results in serious side effects. If co-administration of NEIs could allow people with Duchenne to be on a lower dose of steroids without sacrificing the benefits steroids provide, that would be a great improvement in care.

We are encouraged by the data here and look forward to working with Dr. Pisconti following Tuesday’s presentation to further verify these preliminary findings. We need therapies like this to provide benefits that will complement other treatments in development like gene therapy.

Dr David Bull, our Director of Research, is at the 2019 MDA Scientific Conference in Orlando, Florida and was pleased to meet up with Dr. Dada Pisconti and Charley’s Fund President and COO Laura Dalle Pazze. (Pictured below)

Read more in our Q+A with Dr. Pisconti below to learn why and what’s next:

Q: First, can you give us a quick refresher on the rationale behind this therapeutic approach?

A: Dystrophic muscles have more neutrophil elastase (NE) than normal muscles. Elevated levels of this neutrophil elastase damage the muscle cells, promote chronic inflammation and fibrosis, and prevent muscle stem cells from regenerating the damaged muscle. Given the negative effects that are caused by too much neutrophil elastase in the muscle tissue, it seems like a good idea to test whether inhibiting the protein can help ameliorate the dystrophic condition. This potential treatment approach is especially appealing because there are several drugs in this category that are already being developed for other conditions. If preclinical data looks good, the path to testing in humans is much shorter than it would be for a brand-new molecule that has never been tested in humans.

Q: Without diving too deep, as you review the preliminary data and results, what would you highlight as the early take-home messages?

A: It seems that combining an NEI with prednisolone provides benefits in a Duchenne mouse model. Mice treated with a combination of prednisolone and an NEI did better on multiple measures than mice treated with prednisolone alone or with the NEI alone. Mice treated with the combination had lower levels of CK and TGF-beta, markers of muscle damage and inflammation. They seem to have less fibrosis and better muscle regeneration, but quantification of the latter markers still need more work. Importantly, mice treated with the combination showed improved muscle function as measured by exercise on an activity wheel and hanging bar. Also, very importantly: adding this NEI to chronic steroid treatment appeared to mitigate certain negative side effects of steroids, including liver toxicity.

Q: So, what could this mean in the context of other research that people are so excited about, such as gene therapy?

A: Lack of dystrophin causes a cascade of pathological events, which we know participate in decreasing the efficiency of gene therapy approaches. Combining gene therapy with strategies that reduce fibrosis and inflammation, fortify muscle membranes, and promote muscle regeneration are bound to improve gene therapy efficiency. A successful treatment for DMD will take a 360-degree approach. Inhibiting neutrophil elastase could be an effective tool in the arsenal.

Q: Interestingly, the studies suggest that NE inhibition alone does not appear to provide benefit, but a combination of prednisolone and the NE inhibitor provided more benefit than prednisolone alone. If this proves out in peer review and through further research, will you be surprised by these results?

A: Yes. This is why we are looking more carefully into the fine details of the mechanisms of action of a potential combinatorial therapy featuring a steroid and an NE inhibitor. We are currently working on several hypotheses that might explain these results. Once the current studies are completed, we will have a clearer idea of what the combinatorial therapy is doing in the muscle of dystrophic mice. Hopefully we will find out that the results we are obtaining in mice are indeed translatable to humans.

Q: The data also suggested that a lower dose of the NEI in combination with the steroid performed better than the higher dose. Do you have a hypothesis as to why? What do you need to do to investigate further?

A: Every drug has “good” and “bad” effects, and finding the right dose and time of administration is absolutely critical for a therapeutic regime to maximise the benefits while minimising the side effects. It is possible that if too much NE inhibitor is administered, its side effects begin to prevail over its beneficial effects. At this point, in addition to further investigating the mechanism(s) of action of the two drugs combined, we would also like to test various combinations of the drugs, and especially explore lower doses of both.


NOTES FOR EDITORS

What is Duchenne Muscular Dystrophy?

Duchenne Muscular Dystrophy is the most common fatal genetic disease diagnosed in childhood. Children born with DMD cannot produce the protein dystrophin which is vital for muscle strength and function. Muscle weakness starts in early childhood. Many use a wheelchair by around the age of 12. As deterioration continues it leads to paralysis and early death, often in their 20s. It almost exclusively affects boys. There is no treatment or cure. In the UK there are around 2,500 boys affected and around 300, 000 worldwide. It is classified as a rare disease.

Who are Duchenne UK?

Duchenne UK is a lean, ambitious and highly focused charity with a clear vision: to fund and accelerate treatments and a cure for Duchenne muscular dystrophy. The charity has been formed by the coming together of Joining Jack and Duchenne Children's Trust, the two biggest funders of research in the UK in the last three years. Its president is HRH The Duchess of Cornwall. Its patrons include the broadcasters Krishnan Guru-Murthy and Mary Nightingale, and the sports stars Owen Farrell, Kris Radlinski and Andy Farrell. 

How to donate?

Duchenne UK is entirely reliant on donations to fund research for treatments and a cure to DMD. This can be done via:

  • Direct Debit – Duchenne Direct
  • Individual Donation – Donate
  • If you are a family or friend affected by DMD you can set up your own fund with Duchenne UK – Family and Friend Funds
  • Take part in one of our fundraising events – Events
  • Text DUCHENNE to 70085 to donate £5. This costs £5 plus a std rate msg.

For more information and interview requests:

Visit www.duchenneuk.org

Molly Hunt – Communications Manager, Duchenne UK 

E: [email protected]