After a 30-year wait, the last decade has seen a number of therapies for treating Duchenne muscular dystrophy (DMD) get FDA approval, either by the normal or accelerated pathway, with many more in development.
DMD is a recessive, degenerative muscle disorder that almost exclusively affects males or people with one X chromosome because the genetic mutation that causes the condition is found on the X chromosome. Estimates vary, but it is thought to impact between one in 3,500 and one in 5,000 male births.
Despite the dystrophin gene and its links with DMD being discovered in 1986, it was only in 2016 that eteplirsen, an antisense oligonucleotide (ASO) treatment for DMD patients with mutations amenable to dystrophin exon 51 skipping, was given accelerated FDA approval.
Almost 10 years on, there are now three anti-inflammatory corticosteroids with full FDA approval and four exon-skipping ASOs with accelerated approval. Sarepta’s gene therapy, delandistrogene moxeparvovec (Elevidys), was given expanded approval in June.
While this progress is undoubtedly very promising, there is still a strong unmet need for new therapies to treat this very heterogeneous disease. There are more than 2,000 recorded mutations linked to either DMD or a milder version of the condition known as Becker muscular dystrophy, which can make treatment difficult.
CEO and co-founder
Satellos
Frank Gleeson is the CEO and co-founder of Satellos, a Canadian biotech company that is taking a “dystrophin independent,” small molecule approach to treating DMD. If found to be effective, the company’s therapy could be beneficial regardless of which mutation the patient is carrying.
Gleeson spoke to Inside Precision Medicine senior editor Helen Albert about DMD, the science behind Satellos, what the company hopes to achieve, and what we can expect to see in this space in the future.
Q: How did you get to where you are today?
I created this company with a colleague of mine, Michael Rudnicki in 2018. My background is largely biotech. For the last 30 years, I’ve been involved in various aspects of the biotechnology industry as a venture capitalist, a corporate CEO, and as an entrepreneur, starting companies. Before that, I had a corporate career in industry.
I was attracted to creating Satellos because of the discoveries that my colleague Dr. Rudnicki made. I found that they were so compelling for their potential to change the course of medical practice in an important disease area.
Co-founder and Chief Discovery Officer
Satellos Bioscience
I had never encountered an individual with Duchenne muscular dystrophy before starting the company. Michael had, but only through his scientific research, not because of any family connection. However, we could immediately recognize the potential value and help to patients that this discovery Michael made could yield. It’s a population that is so deserving of help and fight so hard for their own ability to live their lives. What we’ve discovered, we think, can contribute to that in a meaningful way.
Q: How are you approaching treating DMD at Satellos?
The general understanding of Duchenne muscular dystrophy as a genetic disease is that the protein product of the mutated gene [dystrophin] is required to provide stability to the muscle fiber. In essence, that is the disease—the damaged fiber—but what Michael’s discovery taught us is that that’s an incomplete view of the pathology of the disease.
The same protein has a second role in the muscle stem cell itself, where it is not only expressed, but plays a signal transduction role in properly assembling the complex of cells required to establish the mitotic spindle and allow an asymmetric division to occur. It does this by reorienting the spindle in a manner that is perpendicular to the muscle fiber so it changes the polarity of the cell.
In changing the polarity of the cell, the two individual cells that become the progeny are differentiated. One becomes a progenitor muscle cell, and one remains a stem cell to preserve the pool of stem cells. In response to fiber damage, the muscle stem cells literally spring into action, polarize in this fashion, and create new progenitors which become new muscle cells.
In the absence of that polarization, the muscle stem cell more or less becomes lost in space. Over time, what happens is that the bodies of these young people with DMD are not able to keep up with the continuing damage to the muscle fibers.
When Michael explained this to me a decade ago, I was fascinated and we both recognized that this could provide a new way to look at DMD and a new way to treat the disease. For the two of us, who have worked in the stem cell field in different ways for 20 years, it could allow us to test a hypothesis that it would be possible to develop small molecule drugs that can modulate intrinsic stem cell activity.
Q: How does your lead candidate therapy, SAT-3247, target DMD?
It hit us that what dystrophin is doing in the stem cell is providing a signal role. We know an awful lot about signal transduction, there’s a whole body of science that has been built for decades now. We thought, let’s try and marry this together. Let’s see if we can find alternate pathways, alternate signals that we can modulate, that would reestablish polarity.
Starting with these principles, we embarked on a journey of discovery to see if we could do this. It took us a few years, but we did that. We came up with a number of different pathways that could be modulated to alter the polarity of muscle cells and potentially other cells.
In this case, we’re interested in muscle stem cells. From that, we established a number of criteria. For example, we were not interested in pathways that were proliferative in nature and we’re not looking to create more stem cells. We spent quite a bit of time screening and counter-screening and eliminating different approaches. We wanted to find pathways with protein targets that could be druggable, and druggable selectively, so that we would minimize consequential effects.
About a year ago, we identified a small molecule that met all of the criteria targeting a protein known as adaptor-associated kinase one, or AAK1, which is involved in the Notch pathway. From that we have constructed a very rigorous body of knowledge and data illustrating that when we inhibit AAK1, we alter the polarity of muscle stem cells. This leads to asymmetric division being increased and that subsequently leads to more muscle cells being produced.
We’re so excited about what we’re doing and its potential, and we’re now on the verge of commencing our first in human safety studies with our pill.
Q: How do you think this mode of action can help children with this condition?
We really had to spend time trying to convince people that muscle fiber, even without dystrophin (because we’re not trying to put dystrophin back in the body), could be functional.
Children with DMD are able to walk for several years, but they don’t have functional dystrophin. They grow and as they’re growing, they’re creating more muscle. So, it’s clear that their muscle can be functional. We believe that there is a tipping point where the efficiency of the repair process gets overwhelmed by the constant damage. When that happens, we believe the immune system starts to play a negative role, because it thinks the body is under assault. We can see this with upregulation of IgG. Now the body is, in a way, turning on itself.
If you or I have muscle damage, we work out too hard, or we get injured, then unknown to us our stem cells will immediately respond to that damage signal. They will begin to produce new muscle as a result of asymmetric division. We may feel some inflammation, but it’s not taking over the process. Now imagine a situation in which our stem cells are attempting to divide asymmetrically, are failing in the process, and necrosis is beginning to happen. Now you have an inflammatory response that is not positive inflammation, it is now attempting to get rid of the necrotic tissue.
This makes sense to us because children with DMD, over time, lose their muscle. It’s not only that the muscle weakens, it is actually muscle loss. If we can intervene in a way that lessens the formation of necrotic tissue because we’re helping the cells to divide properly, then we speculate that the immune system does not need to “bring in the troops,” so to speak.
We think that this may be in part how corticosteroids have played a helpful role, because they’re clearly abating that inflammatory response, and we infer that it’s allowing the muscle to continue to function for a little longer before it becomes overwhelmed by the degree of damage again.
Q: Is anyone else working on similar research to Satellos?
Louis Kunkel and his collaborator Mayana Zatz reported in Cell in 2015 on escape in golden retriever dogs. These were dogs in a colony of dystrophin null animals [a model of DMD] that lived a normal life. In their paper, they postulated that regeneration was enhanced in these animals through increased expression of the Jagged1 gene, a regulator of Notch signaling.
Subsequently, they’ve identified humans who have essentially escaped the [disease] effects as well. They live more or less a normal life, not fully healthy, but a much-enhanced life. They’re able to ambulate for many more years [than children with classic DMD] and again, Notch was involved, specifically the Notch isoform that’s expressed in muscle stem cells.
We identified all of this quite independently, but we think these papers are providing genetic proof of concept for what we’re trying to do.
Q: There has been quite a lot of movement in this space recently. How do you feel your treatment will stand out compared with other therapies if it reaches the market?
What we’re trying to do is develop a very simple to administer drug that, so far in all of our preclinical work, has revealed itself to be very safe and highly tolerable. Many of the medications that are in development continue to have a side effect profile that, let’s just say, is less than desirable in a patient population that’s severely compromised.
If you’re a person who’s in a wheelchair and the side effect means that you have to go to the bathroom every 10 minutes, that’s not exactly an easy side effect to contend with. So, we have to be really careful about all of these drugs and think where they might fit in a complete pharmacopeia.
I think there will be many drugs that will be required over time that will all fit into their place as new approaches come forward. We see our approach as one that, if we’re correct, can regenerate muscle and easily complement adjuvant therapy, or even act as a standalone therapy.
We think patients and families will be attracted to the ease of administration and the prospect of a really benign side effect profile, which is what we’ve worked really hard to design.
Our medication is also dystrophin independent, so it doesn’t matter what the mutation is. It doesn’t matter if there’s some dystrophin or no dystrophin, because what we’re doing is enhancing the efficiency of the regeneration process. We’re enhancing the efficiency of polarization of the stem cell and we have shown in our animal models that in non-disease situations where muscle is injured, we can improve the efficiency of the polarization and recovery process because it’s not dystrophin dependent.
Our candidate drug is a small molecule. So, from a cost point of view, it’s very attractive, but at this point it’s too early for us to start detailed costing. What we’re trying to do now is get the drug advanced and get the drug approved and show that it can benefit people.
Q: Are you investigating other indications for SAT-3247?
Yes. We’re looking at other dystrophies, which is a natural kind of extension. We’re looking at healthy situations where muscle is injured, and we will continue to look at those kinds of applications. It could be very broadly applied.
For instance, in the field of cancer, we know that in many situations muscle is destroyed by the cancer and the process by which the cancer alters regeneration is to downregulate dystrophin in stem cells. It’s really fascinating that cancer has figured this out before we did, that there is a mechanism that it co-opts to impair regeneration and that’s why people lose muscle mass in cancer. In some cases that progressive loss of muscle causes death before the cancer does.
Q: What are you hoping to see in this field of DMD treatments in the next 5–10 years?
We want to see the disease course altered, so that’s our objective. We, and others in the space, want to alter the course of the disease so that individuals who are diagnosed or already living with the disease at a later stage can see the possibility of their life, and their ability to function, changing. Perhaps older individuals can at least have the hope of not losing more function or of stabilizing. That’s what we would like to see and, over time, we’d like to see ways in which different approaches can be used as part of a pharmacopeia to most benefit individual patients.
Helen Albert is senior editor at Inside Precision Medicine and a freelance science journalist. Prior to going freelance, she was editor-in-chief at Labiotech, an English-language, digital publication based in Berlin focusing on the European biotech industry. Before moving to Germany, she worked at a range of different science and health-focused publications in London. She was editor of The Biochemist magazine and blog, but also worked as a senior reporter at Springer Nature’s medwireNews for a number of years, as well as freelancing for various international publications. She has written for New Scientist, Chemistry World, Biodesigned, The BMJ, Forbes, Science Business, Cosmos magazine, and GEN. Helen has academic degrees in genetics and anthropology, and also spent some time early in her career working at the Sanger Institute in Cambridge before deciding to move into journalism.
