Small molecule regenerative therapies with Angela Russell
At the 256th National Meeting and Exposition of the American Chemical Society we spoke to Angela Russell, Professor of Medicinal Chemistry at the University of Oxford, to learn more about her research into small molecule-based regenerative therapies.
Could you please introduce yourself and tell us about your background?
I’m Professor Angela Russell; a Professor of Medicinal Chemistry at the University of Oxford (UK), with a joint appointment in chemistry and pharmacology. I was trained as a synthetic chemist but I’ve always known that I wanted to do research at the interface of chemistry and medicine; I was awarded a Research Councils fellowship in the UK and ultimately that ran into a tenure track position at Oxford.
I started out my independent career thinking that I wanted to try to use chemistry to understand problems that were intractable in biological systems. One of the questions we set about asking was how can we control the decisions that a cell makes, in terms of its fate: whether it dies, whether it becomes a certain cell type, whether it differentiates, and that was very interesting at a fundamental level, but what we very quickly realized was that it was extremely relevant and important in medicine.
We had a very different idea about how we wanted to develop/translate our small molecules into medicines; most other people have started thinking about how to use chemistry to manipulate cells outside of the body and then use them for transplantation. Our own approach is completely different. We know now that most of those cells when you implant them into the body actually don’t engraft – it’s not a cell replacement but rather they stimulate innate repair processes, so why couldn’t we think about developing a medicinal chemistry regenerative medicine strategy where we develop an agent that actually harnesses those repair processes directly?
So that’s what my research group does, and encompasses what I’m talking about.
You presented a talk at the ACS Fall Meeting entitled ‘Small molecule utrophin modulators for the therapy of Duchenne Muscular Dystrophy.’ Can you give us an overview of your presentation?
I certainly can – it is actually the precursor to the main focus of my research now.
This is a project I’ve been involved in for over 15 years in collaboration with a group in Oxford led by Professor Dame Kay Davies in the Department of Physiology, Anatomy and Genetics. She discovered that in Duchenne Muscular Dystrophy (DMD), which is a disease caused by a defective muscle protein, there is, in fact, a compensatory protein (utrophin) already encoded within our genomes. Her idea was that if we could actually replace the defective protein with this compensatory protein that might be a therapy relevant for all patients with DMD.
So 15 years ago we set about trying to look for a small molecule that could switch on the production of this protein, ultimately, in patients. It was a revolutionary idea at the time, not only that one might be able to use a backup mechanism to compensate for some defective genetic pathway, but more particularly that one might be able to develop a small molecule therapeutic to do this. This was unheard of at the time we proposed our research and people didn’t think it would be feasible or safe if we were able to do it.
We were really convinced it was the right approach; the main reason for that was this is a disease that affects all muscles, and that’s 40% body mass. It affects the heart, it affects the diaphragm and we now know it affects elements within the brain as well, so we needed something that was going to be readily available systemically. We thought a small molecule was the best way to go about it from a practical perspective.
The talk that I gave described the early evidence behind why this was a reasonable therapeutic approach, our early endeavors at looking for small molecules and ultimately the clinical development of a compound that went into a Phase II clinical trial in 2016. It unfortunately didn’t meet its primary endpoints, but we don’t believe that is because the hypothesis is at fault, rather it was the wrong compound.
The last part of my talk was describing how we’ve gone back to look for other molecules and mechanisms that can elicit the same response because we think they will have a better chance of making it in a clinical setting.
What is it about this research that most excites you?
For me, it was that it was groundbreaking. I’m someone who would always like to go and do something, especially if someone tells me it can’t be done. But also, there was a strong motivation because this is a devastating disease that affects 1 in 5000 live male births. There’s a huge unmet medical need; these boys are in wheelchairs by the time they’re in their teens, and they usually die in their 20s or early 30s.
The only thing that’s out there for them at this moment is symptomatic relief: steroids and physical supports and so on. So, to actually go out there and try and be able to address something that fixes the root cause of the disease was a tremendous challenge, but also could seriously benefit – and will ultimately benefit – this patient population.
What is the focus of your current research? Are you working on any other projects?
What my research led into was a regenerative medicine, and really the work that I presented at the ACS National Meeting and Exposition was the underpinning science behind that.
What we hadn’t appreciated when we started out on the endeavor was that utrophin is involved not only in muscle generation and development in the first instance, but actually it’s involved in muscle regeneration as well. We realized that this is a paradigm that is relevant not only in muscle but in all sorts of other tissues; one uses the same pathways to develop tissues as one then uses to regenerate tissues later in life, in the case of injury or similar.
What we’d done inadvertently was to develop something that could pharmacologically modulate that process – that’s not to say that utrophin modulators are a regenerative therapy, suggesting that one could potentially develop an agent that could reactivate these developmental gene programs.
As I say, it’s not just relevant in muscle but also in all sorts of other tissues, so we wondered if it was possible to develop small molecules to target these pathways in the brain and stimulate new neuron production. Could that rescue cognitive deficits in neurodegenerative conditions, neural injury or even neuro-psychiatric disorders? And that’s one example of what we’ve gone on to do.
So, the majority of the work in my group now – is focused on extending that paradigm into regenerative medicine, which for me is totally unchartered territory, and that’s really exciting.
What have you enjoyed most about ACS Boston?
I always enjoy coming to the ACS meetings because they are so diverse – maybe they’re a bit too big but nonetheless you get to see a whole breadth of science. What I particularly enjoyed this year is that there have been a huge number of talks targeting orphan and rare diseases, and that’s very unusual.
I think that is very encouraging, it speaks a lot to what’s going on in the medicinal chemistry field. Scientists are realizing there is a need to go after these diseases and researchers are making real progress towards translating their findings to clinical benefit. I was in a session of five talks and every single person talked about the clinical testing of their product, which was fabulous to see.