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Towards Treatment for Leukodystrophy

Can you introduce your company?

The story begins with a former colleague of mine at Immunocore.

Her daughter has a disease called H-ABC (hypomyelination with atrophy of the basal ganglia and cerebellum) – a form of leukodystrophy caused by the gene TUBB4A. After learning of her daughter’s diagnosis, my colleague responded – not just as a mother but also as a scientist.

She investigated existing treatments and research, then set up a charity, all before sitting down with me to have a good think about how we could produce the therapy her child needed. That’s how we ended up setting up SynaptixBio. 

What’s your background?

I’m a trained scientist. I spent the better part of 10 years at Dundee University in the UK, studying biochemistry and working toward my PhD. After my studies, I joined a very small start-up called Avidex. Over time, I progressed from the bench to leadership. 

For the remainder of my first two decades post-academia, I worked in T-cell therapy development. I went from Avidex to MediGene, and then on to Adaptimmune, where my final role was vice president of research operations and technology. 

After that came SynaptixBio.

Could you tell us more about leukodystrophy?

It’s helpful to think of leukodystrophy as a spectrum of severity. At the severe end of the spectrum, babies born with the disease have developmental and motor issues. 

With H-ABC – which is just as severe – the mutation forms within the children and they start to undergo myelin degradation, and again we see developmental delays and deterioration of motor functions. This usually starts at five to eight years old but it can continue through to the mid-to-late teens. Often, the disease is fatal.

There are also other forms of TUBB4A leukodystrophy that are less severe, but still affect quality of life. 

Our aim is to alleviate the decline in quality of life faced by these patients – and potentially increase their life expectancy. If we can stabilize the disease outright that would be even better. Clinical trials will show us whether that level of success is possible.

How do you plan to tackle these diseases? 

The starting point is our understanding of the root cause of the disease – in this case, a mutation in the TUBB4A gene. The mutation causes the formation of an abnormal protein, which then fails in its task of transporting various fats, lipids, and proteins used to produce myelin – a fatty substance that insulates nerves and causes the white hue in our brains.

Put simply, the formation of the myelin is compromised, meaning that the signals traveling back and forth along the central nervous system are disrupted. Patients start to suffer from problems with movement and can also experience seizures or developmental delays.

SynaptixBio is trying to develop a gene therapy that will silence the expression of the abnormal protein to allow another protein to step in to support production of myelin, in turn alleviating those symptoms.

The type of molecule under investigation is an antisense oligonucleotide (ASO), which binds to and inhibits the mutated TUBB4a messenger RNA encoding the abnormal protein. When bound, the cells cannot make the toxic mutant.

However, we don’t yet know to what extent we can actually silence the gene, and we don’t know the full mechanism of action.

What other challenges await SynaptixBio – and you personally as the CEO of a new company?

One key question we’re trying to answer is: How many patients are out there? TUBB4A leukodystrophy is a rare disease, but it is not ultra-rare. As we examine the literature, we are finding that the numbers are higher than they first appeared. From personal experience, I can say that I’ve met a number of children in the south of England with the condition. And that’s just one region in one country.

Pre-seed funding has been essential in helping us launch the company by paying for licenses and researchers. We currently remain privately funded, but we are gearing ourselves up for a further round of funding in the very near future, which would take us to the next phase, before being followed by the clinic. 

Going down that road, we’ll certainly encounter challenges, but also learning opportunities. We have good data, and we have our future spending mapped out, so I believe our position is strong. As CEO, I really enjoy contributing to every aspect of the business. I’m involved with the science, operations, development, and financial strategies. It is certainly a huge challenge, but I’m surrounded by incredible people.

How has your company navigated the pandemic?

Fortunately for us, we are a very small company, and we’re almost entirely virtual. We don’t actually have labs. We are outsourcing and partnering at the moment. Working from home and meeting in Zoom has worked well for us, but we did miss the upsides of face-to-face communication. I will also say that my dog deserves some of the credit. On a typical working day he’s with me in my home office – either curled up on the sofa or demanding walks for our mutual sanity.

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